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.This research has been made possible with the financial support received from the University of Alicante (VIGROB-316FI), the Spanish Ministerio de Ciencia e Innovación (PID2021-127332NB-I00) and the Valencian Department of Innovation, Universities, Science and Digital Society (APOSTD/2020/235 and AICO/2021/013)

Cross-dehydrogenative coupling reaction using copper oxide impregnated on magnetite in deep eutectic solvents

The synthesis of different tetrahydroisoquinolines using choline chloride : ethylene glycol as a deep eutectic solvent (DES) and copper(II) oxide impregnated on magnetite as a catalyst has been accomplished successfully. The copper catalyst amount is the lowest loading ever reported. The presence of DES showed to be essential since the reaction in the absence of this medium did not proceed. A direct proportional relationship was found between the conductivity of DES medium and the yield obtained. The DES and the catalyst could be reused up to ten times without any detrimental effect on the yield of the reaction, with the aerobic conditions making the protocol highly sustainable, where the only waste is water.This work was supported by the Spanish Ministerio de Economía y Competitividad (MICINN; CTQ2011-24151) and the University of Alicante. J. M. P. thanks the MICINN (FPI program) for her fellowship

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.This work was supported by the University of Alicante (UAUSTI16-10, VIGROB-173), and the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P). X.M. thanks Generalitat Valenciana (ACIF/2016/057) for fellowship

Visible-Light-Mediated Amide Synthesis in Deep Eutectic Solvents

In the present study, for the first time environmentally friendly deep eutectic solvents (DESs) are used as reaction media to perform an efficient, simple and straightforward photocatalytic amide synthesis at room temperature using thioacids and amines. This method features mild conditions, a broad substrate scope, high yields (≤99%) under ambient conditions with air and moisture tolerance. Moreover, the applied operationally mild reaction conditions tolerate the presence of several different functional group substituents on the amine counterpart. Finally, the developed approach allows the recycling of the reaction medium and catalyst for at least three consecutive cycles without a significant decrease in the reaction yield.This research has been made possible thanks to the financial support received from the University of Alicante (VIGROB-316FI), the Spanish Ministerio de Ciencia e Innovación (PID2021-127332NB-I00) and the Valencian Department of Innovation, Universities, Science and Digital Society (APOSTD/2020/235 and AICO/2021/013). The authors thank the Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence funded according to the Law 232/2016) of the University of Calabria (Italy)

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.This work was supported by the University of Alicante (VIGROB-173 and VIGROB-309), the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P, PGC2018-096616-B-I00 and RTI2018-099860-B-I00). X.M. and J.T. C. thank Generalitat Valenciana (ACIF/2016/057 and ACIF/2016/077) for their fellowships

NCN–Pincer–Pd Complex as Catalyst for the Hiyama Reaction in Biomass-Derived Solvents

A NCN–pincer–Pd complex has been synthesized and applied to Hiyama-type cross-coupling reactions between aryl halides and different types of organosilanes using neoteric solvents. This report constitutes a green approach to cross-coupling reactions since the reagents employed are stable and nontoxic. The solvents used (deep eutectic solvents based on choline chloride or glycerol) are also biodegradable, nontoxic, nonflammable, and biorenewable. Furthermore, the catalytic system can be recycled, allowing us to perform the reaction for at least three cycles without adding more catalyst or solvent, increasing the value of the process from an economical and environmental point of view. The effect of these solvents on the catalytic activity has been studied. Finally, a gram-scale reaction has also been tested affording biaryl products in high yields and purity by a simple liquid–liquid extraction, without the need of aqueous workup or chromatographic steps, proving the applicability of this approach in a sustainable industrial scale.This work was supported by the University of Alicante (VIGROB-173) and the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P). X.M. thanks Generalitat Valenciana (ACIF/2016/057) for a fellowship

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.This work was supported by the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P and PGC2018-096616-B-I00) and the University of Alicante (VIGROB-316)

Deep Eutectic Solvents: À la Carte Solvents for Cross-Coupling Reactions

En la presente memoria se describe el uso de líquidos eutécticos sostenibles (DESs en inglés) como medios de reacción, empleando diferentes catalizadores metálicos para llevar a cabo la síntesis de compuestos orgánicos de interés en química orgánica. En el Primer Capítulo se detalla el uso de un catalizador heterogéneo de cobre soportado sobre magnetita en el acoplamiento cruzado deshidrogenante de tetrahidroisoquinolinas en mezclas eutécticas. En el Segundo Capítulo se pormenoriza sobre la síntesis de un complejo tipo pinza de paladio y su empleo en la reacción de acoplamiento cruzado de Hiyama, tanto en mezclas eutécticas como en glicerol, como medios sostenibles de reacción. Asimismo, y con el fin de mejorar la compatibilidad de los catalizadores de paladio en estos líquidos eutécticos, se detalla el diseño y la síntesis de fosfinas catiónicas, las cuales han probado su efectividad como ligandos de paladio en reacciones típicas de acoplamiento cruzado (Suzuki, Heck y Sonogashira) en diferentes mezclas eutécticas. Finalmente, en el Tercer Capítulo se describen reacciones multicomponente de acoplamiento cruzado para la formación de enlaces C-S. Por un lado, se ha desarrollado una metodología para la inserción de SO2 catalizada por paladio a partir de ácidos borónicos y metabisulfito de sodio. Por otro lado, una variante de la metodología anterior permitió la síntesis de sulfonamidas sustituyendo los ácidos borónicos por compuestos de triarilbismuto y nitrocompuestos bajo catálsis de cobre. En este último caso, una nueva mezcla eutéctica ha sido descrita y caracterizada, tanto físco-química como biológicamente

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 of Ag salts. The use of the eutectic mixtures improves the yields obtained with volatile organic solvents, and allows to reuse the catalyst. Post-synthetic modifications can also be performed in DESs, increasing the sustainablility of the process and the value of the products obtained.This research has been made possible thanks to the financial support received from the University of Alicante (VIGROB-316FI) and the Spanish Ministerio de Industria y Competitividad (PGC2018-096616-B-I00) and the Valencian Department of Innovation, Universities, Science and Digital Society (APOSTD/2020/235 and AICO/2021/013)

Deep Eutectic Solvents: À la Carte Solvents for Cross-Coupling Reactions

En la presente memoria se describe el uso de líquidos eutécticos sostenibles (DESs en inglés) como medios de reacción, empleando diferentes catalizadores metálicos para llevar a cabo la síntesis de compuestos orgánicos de interés en química orgánica. En el Primer Capítulo se detalla el uso de un catalizador heterogéneo de cobre soportado sobre magnetita en el acoplamiento cruzado deshidrogenante de tetrahidroisoquinolinas en mezclas eutécticas. En el Segundo Capítulo se pormenoriza sobre la síntesis de un complejo tipo pinza de paladio y su empleo en la reacción de acoplamiento cruzado de Hiyama, tanto en mezclas eutécticas como en glicerol, como medios sostenibles de reacción. Asimismo, y con el fin de mejorar la compatibilidad de los catalizadores de paladio en estos líquidos eutécticos, se detalla el diseño y la síntesis de fosfinas catiónicas, las cuales han probado su efectividad como ligandos de paladio en reacciones típicas de acoplamiento cruzado (Suzuki, Heck y Sonogashira) en diferentes mezclas eutécticas. Finalmente, en el Tercer Capítulo se describen reacciones multicomponente de acoplamiento cruzado para la formación de enlaces C-S. Por un lado, se ha desarrollado una metodología para la inserción de SO2 catalizada por paladio a partir de ácidos borónicos y metabisulfito de sodio. Por otro lado, una variante de la metodología anterior permitió la síntesis de sulfonamidas sustituyendo los ácidos borónicos por compuestos de triarilbismuto y nitrocompuestos bajo catálsis de cobre. En este último caso, una nueva mezcla eutéctica ha sido descrita y caracterizada, tanto físco-química como biológicamente