Continuous Flow Processes as an Enabling Tool for the Synthesis of Constrained Pseudopeptidic Macrocycles.

Herein we report our efforts to develop a continuous flow methodology for the efficient preparation of pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo-[3,4-f]-isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Appropriate design of a supported base permitted the continuous production of the macrocycles even at large scales, taking advantage of the positive template effect promoted by the bromide anions. In addition, the use of flow protocols allowed a ca. 20-fold increase in productivity as well as reducing the environmental impact almost 2 orders of magnitude, in comparison with the related batch macrocyclization process.

Basically, nucleophilicity matters little: towards unravelling the supramolecular driving forces in enzyme-like CO2 conversion.

The reaction mechanism for the cycloaddition of CO2 to styrene oxide in the presence of macrocyclic pseudopeptides has been studied using DFT methods. Computational calculations indicate that the unprecedented catalytic behaviour previously observed experimentally, in which the most reactive species was not the most nucleophilic but the most basic one, can be associated to the tight cooperativity between several supramolecular interactions promoted by simple peptidomimetics able to display a synzymatic behaviour. This bizarre catalytic performance afforded remarkable conversions of a sluggish substrate like styrene oxide into the desired cyclic carbonate, even under relatively mild reaction conditions, opening the way for the practical use of CO2 as a raw material in the preparation of valuable chemicals. Furthermore, the remote modification of essential structural features of the macrocycle (synzyme engineering) permitted the driving forces of the synzymatic system to be analyzed, stressing the crucial synergic effect between an elegantly preorganized oxyanion hole and additional aromatic interactions.

Structure-antitumor activity relationships of tripodal imidazolium-amino acid based salts. Effect of the nature of the amino acid, amide substitution and anion.

The antitumor activity of imidazolium salts is highly dependent upon their lipophilicity that can be tuned by the introduction of different hydrophobic substituents on the nitrogen atoms of the imidazolium ring of the molecule. Taking this into consideration, we have synthesized and characterized a series of tripodal imidazolium salts derived from L-valine and L-phenylalanine containing different hydrophobic groups and tested them against four cancer cell lines at physiological and acidic pH. At acidic pH (6.2) the anticancer activity of some of the tripodal compounds changes dramatically, and this parameter is crucial to control their cytotoxicity and selectivity. Moreover, several of these compounds displayed selectivity against the control healthy cell line higher than four. The transmembrane anion transport studies revealed moderate transport abilities suggesting that the observed biological activity is likely not the result of just their transport activity. The observed trends in biological activity at acidic pH agree well with the results for the CF leakage assay. These results strongly suggest that this class of compounds can serve as potential chemotherapeutic agents.

Correction: Free ion diffusivity and charge concentration on cross-linked polymeric ionic liquid iongel films based on sulfonated zwitterionic salts and lithium ions.

Correction for 'Free ion diffusivity and charge concentration on cross-linked polymeric ionic liquid iongel films based on sulfonated zwitterionic salts and lithium ions' by David Valverde et al., Phys. Chem. Chem. Phys., 2019, 21, 17923-17932, DOI: 10.1039/C9CP01903K.

Chiral Imidazolium Prolinate Salts as Efficient Synzymatic Organocatalysts for the Asymmetric Aldol Reaction.

Chiral imidazolium l-prolinate salts, providing a complex network of supramolecular interaction in a chiral environment, have been studied as synzymatic catalytic systems. They are demonstrated to be green and efficient chiral organocatalysts for direct asymmetric aldol reactions at room temperature. The corresponding aldol products were obtained with moderate to good enantioselectivities. The influence of the presence of chirality in both the imidazolium cation and the prolinate anion on the transfer of chirality from the organocatalyst to the aldol product has been studied. Moreover, interesting match/mismatch situations have been observed regarding configuration of chirality of the two components through the analysis of results for organocatalysts derived from both enantiomers of prolinate (R/S) and the trans/cis isomers for the chiral fragment of the cation. This is associated with differences in the corresponding reaction rates but also to the different tendencies for the formation of aggregates, as evidenced by nonlinear effects studies (NLE). Excellent activities, selectivities, and enantioselectivities could be achieved by an appropriate selection of the structural elements at the cation and anion.

Rational Design of Simple Organocatalysts for the HSiCl3 Enantioselective Reduction of (E)-N-(1-Phenylethylidene)aniline.

Prolinamides are well-known organocatalysts for the HSiCl3 reduction of imines; however, custom design of catalysts is based on trial-and-error experiments. In this work, we have used a combination of computational calculations and experimental work, including kinetic analyses, to properly understand this process and to design optimized catalysts for the benchmark (E)-N-(1-phenylethylidene)aniline. The best results have been obtained with the amide derived from 4-methoxyaniline and the N-pivaloyl protected proline, for which the catalyzed process is almost 600 times faster than the uncatalyzed one. Mechanistic studies reveal that the formation of the component supramolecular complex catalyst-HSiCl3-substrate, involving hydrogen bonding breaking and costly conformational changes in the prolinamide, is an important step in the overall process.

Highly Selective Anion Template Effect in the Synthesis of Constrained Pseudopeptidic Macrocyclic Cyclophanes.

Herein, we report the synthesis of a novel family of constrained pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo[3,4-f]isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Although the increase in the number of steps involved in the macrocyclization could lead to a larger number of possible side products, the optimization of the methodology and the study of the driving forces have made it possible to obtain the desired macrocycles in excellent yields. A thorough computational study has been carried out to understand the macrocyclization process, and the results obtained nicely agree with experimental data. Moreover, the bromide anion had a clear catalytic template effect in the macrocyclization reaction, and surprisingly, the chloride anion had a negative template effect in opposition to the results obtained for analogous macrocycles. The parameters responsible for the specific kinetic template effect observed have been studied in detail.

Synergy between supported ionic liquid-like phases and immobilized palladium N-heterocyclic carbene-phosphine complexes for the Negishi reaction under flow conditions.

The combination of supported ionic liquids and immobilized NHC-Pd-RuPhos led to active and more stable systems for the Negishi reaction under continuous flow conditions than those solely based on NHC-Pd-RuPhos. The fine tuning of the NHC-Pd catalyst and the SILLPs is a key factor for the optimization of the release and catch mechanism leading to a catalytic system easily recoverable and reusable for a large number of catalytic cycles enhancing the long-term catalytic performance.

Free ion diffusivity and charge concentration on cross-linked polymeric ionic liquid iongel films based on sulfonated zwitterionic salts and lithium ions.

The properties of various mixtures of a zwitterionic ionic liquid (ZIs-1) and LiNTf2, including their conductivity, have been studied showing how they can be adjusted through their molar composition. Conductivity tends to increase with the LiNTf2 content although it presents a minimum at the region close to the eutectic point. These mixtures also provide excellent features as liquid phases for the preparation of composite materials based on crosslinked PILs. The prepared films display excellent and tuneable properties as conducting materials, with conductivities that can be higher than 10-2 S cm-1 above 100 °C. The selected polymeric compositions show very good mechanical properties and thermal stability, even for low crosslinking degrees, along with a suitable flexibility and good transparency. The final properties of the films correlate with the composition of the monomeric mixture used and with that of the ZIs-1:LiNTf2 mixture.

Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst.

Positive effects of the polymeric support on the performance of supported chiral catalysts, in terms of activity, stability and selectivity-enantioselectivity, have been reported when the support is properly selected and optimized opening the way to the design of more efficient catalytic systems.

Chiral imidazolium receptors for citrate and malate: the importance of the preorganization.

A family of simple receptors formed by two or three cationic imidazolium arms attached to a central aromatic linkage and displaying different conformational flexibility has been synthesized from the enantiopure (1S,2S)-2-(1-H-imidazol-1-yl)-cyclohexanol. The crystal structures of the corresponding bromides of two of the hosts showed remarkable differences. The tripodal receptor with a trimethylated central benzene ring (1a) showed a cone-type conformation defining an inner anion-binding site, while the bipodal molecule with the central meta-phenylene spacer (m-2a) displayed an extended conformation. The binding properties of the chiral imidazolium hosts toward citrate, isocitrate and the two enantiomers of malate have been studied by (1)H NMR titration experiments in 9:1 CD3CN:CD3OH at 298.15 K. Interestingly, 1a showed a stronger interaction with dianionic malate than with the trianionic citrate or isocitrate, suggesting that the smaller guest is better accommodated in the host cavity. Among this family, 1a proved to be the best receptor due to a combination of a larger number of electrostatic and H-bonding interactions and to a more efficient preorganization in the cone-type conformation. This preorganization effect is also present in solution as confirmed by (1)H NMR spectroscopy.

Pd-imidate@SBA-15: a multifunctional heterogeneous catalyst for the aqueous room temperature hydrogenation of CO2 to formic acid.

The incorporation of hydrophilic and basic sites from phosphotriazaadamantane and saccharine in a water-soluble Pd complex and the subsequent confinement into mesoporous silica support increases the activity and stability of the palladium catalytic species for the room-temperature aqueous hydrogenation of either bicarbonate or CO2 into formic acid. The use of low Pd loadings (<0.1mmolPd·g-1) of the well-dispersed complex on SBA-15 mesoporous silica allows performing the reaction under room temperature, and aqueous conditions, exhibiting TON of ca. 40-100, for the CO2 or bicarbonate hydrogenation, respectively, which is one order of magnitude higher than the homogeneous case, allowing the easy isolation and recycling of the solid catalyst.

Chiral triazolium salts and ionic liquids: from the molecular design vectors to their physical properties through specific supramolecular interactions.

An exhaustive experimental study based on X-ray diffraction analysis, NMR, FTIR-ATR (attenuated total reflection), and Raman spectroscopy as well as theoretical calculations is reported in order to understand how the non-covalent intermolecular contacts are fundamental to explain structure-property relationships and allowing us to correlate a basic macroscopic property (i.e., the melting point, T(m)) with the structural variables of a family of enantiopure 1,4-dialkyl-1,2,4-triazolium salts. The effect of different structural vectors such as the ring size, the spatial disposition of the substituent, the substitution on the oxygen atom, the nature of the anion, or the N4 alkylation of the triazole on the intermolecular interactions of these chiral salts of a well-defined 3D structure is reported. The non-covalent intermolecular contacts mainly implicating the triazolium H3 proton are fundamental to explain structure-property relationships and, therefore, the physical properties of these new chiral salts, rather than simple anion-cation interactions. Overall, our findings highlight the importance of the specific supramolecular interactions for the understanding of the physical properties of triazolium salts and ionic liquids.

Direct Air Capture and Integrated Conversion of Carbon Dioxide into Cyclic Carbonates with Basic Organic Salts.

Direct air capture and integrated conversion is a very attractive strategy to reduce CO2 concentration in the atmosphere. However, the existing capturing processes are technologically challenging due to the costs of the processes and the low concentration of CO2. The efficient valorization of the CO2 captured could help overcome many techno-economic limitations. Here, we present a novel economical methodology for direct air capture and conversion that is able to efficiently convert CO2 from the air into cyclic carbonates. The new approach employs commercially available basic ionic liquids, works without the need for sophisticated and expensive co-catalysts or sorbents and under mild reaction conditions. The CO2 from atmospheric air was efficiently captured by IL solution (0.98 molCO2/molIL) and, subsequently, completely converted into cyclic carbonates using epoxides or halohydrins potentially derived from biomass as substrates. A mechanism of conversion was evaluated, which helped to identify relevant reaction intermediates based on halohydrins, and consequently, a 100% selectivity was obtained using the new methodology.

Sustainable Setups for the Biocatalytic Production and Scale-Up of Panthenyl Monoacyl Esters under Solvent-Free Conditions.

A sustainable scaling-up process for the biocatalytic production of new bioactive provitamin-B5 monoacyl esters has been demonstrated. A solvent-free reaction protocol, based on the formation of eutectic mixtures between neat substrates, renders highly efficient direct esterification of free fatty acids (i.e., from C6 to C18 alkyl-chain length) with panthenol catalyzed by lipase. The scale-up from 0.5 to 500 g was evaluated by means of using several reaction systems (i.e., ultrasound assistance, orbital shaking, rotary evaporator, and mechanical stirring coupled to vacuum). For all reactor systems, the yield in panthenyl monoacyl esters was improved by increasing the length of the alkyl chain of the fatty acid (i.e., from 63% yield for panthenyl butyrate to 83% yield for panthenyl myristate). The best results (87-95% product yield, for all cases) were obtained upon a scale-up (50-500 g size) and when a vacuum system was coupled to the biocatalytic reaction unit. Under the optimized conditions, a 5-fold reduction of the amount of biocatalysts with respect to reactors without vacuum was achieved. The recovery and reuse of the immobilized enzyme for five operation cycles were also demonstrated. Finally, different metrics have been applied to assess the greenness of the solvent-free biocatalytic synthesis of panthenyl monoesters here reported.

The key role of pretreatment for the one-step and multi-step conversions of European lignocellulosic materials into furan compounds.

Nowadays, an increased interest from the chemical industry towards the furanic compounds production, renewable molecules alternatives to fossil molecules, which can be transformed into a wide range of chemicals and biopolymers. These molecules are produced following hexose and pentose dehydration. In this context, lignocellulosic biomass, owing to its richness in carbohydrates, notably cellulose and hemicellulose, can be the starting material for monosaccharide supply to be converted into bio-based products. Nevertheless, processing biomass is essential to overcome the recalcitrance of biomass, cellulose crystallinity, and lignin crosslinked structure. The previous reports describe only the furanic compound production from monosaccharides, without considering the starting raw material from which they would be extracted, and without paying attention to raw material pretreatment for the furan production pathway, nor the mass balance of the whole process. Taking account of these shortcomings, this review focuses, firstly, on the conversion potential of different European abundant lignocellulosic matrices into 5-hydroxymethyl furfural and 2-furfural based on their chemical composition. The second line of discussion is focused on the many technological approaches reported so far for the conversion of feedstocks into furan intermediates for polymer technology but highlighting those adopting the minimum possible steps and with the lowest possible environmental impact. The focus of this review is to providing an updated discussion of the important issues relevant to bringing chemically furan derivatives into a market context within a green European context.

Tuning Ni-Pyrazolate Frameworks by Post-Synthetic Fe-Incorporation for Oxidase-Mimicking H2 O2 Activation.

The introduction of iron ionic sites by metal exchange of defective homometallic nickel pyrazolate frameworks generates non-precious, Earth-abundant, first-row heterometallic Fe/Ni-pyrazolate frameworks. The Fe incorporation at the Ni nodes of the framework allows to control the hydrogen peroxide activation, minimizing its decomposition and O2 liberation, occurring at the homometallic Ni nodes. The generation of Fe-OH reactive oxygen species at the heterometallic Fe/Ni nodes is demonstrated by the higher activity in the proof-of-concept oxidation of 1-phenylethanol to acetophenone in an aqueous medium.

Supercritical synthesis of biodiesel.

The synthesis of biodiesel fuel from lipids (vegetable oils and animal fats) has gained in importance as a possible source of renewable non-fossil energy in an attempt to reduce our dependence on petroleum-based fuels. The catalytic processes commonly used for the production of biodiesel fuel present a series of limitations and drawbacks, among them the high energy consumption required for complex purification operations and undesirable side reactions. Supercritical fluid (SCF) technologies offer an interesting alternative to conventional processes for preparing biodiesel. This review highlights the advances, advantages, drawbacks and new tendencies involved in the use of supercritical fluids (SCFs) for biodiesel synthesis.

Unravelling the Supramolecular Driving Forces in the Formation of CO2-Responsive Pseudopeptidic Low-Molecular-Weight Hydrogelators.

A new family of C2-symmetric pseudopeptides with a high functional density for supramolecular interactions has been synthetized through the attachment of four amino acid subunits to a diamino aliphatic spacer. The resulting open-chain compounds present remarkable properties as low-molecular-weight hydrogelators. The self-assembled 3D networks were characterized by SEM analyses, observing regular nanofibres with 80-100 nm diameters. Spectroscopic and molecular modelling experiments revealed the presence of strong synergic effects between the H-bonding and π-π interactions, with the best results obtained for the homoleptic tetra-pseudopeptide derived from l-Phe. In addition, these bioinspired hydrogels possessed pH- and CO2-responsive sol-gel transitions. The formation of ammonium carbamate derivatives in the presence of carbon dioxide led to a detrimental change in its adequate self-assembly. CO2 desorption temperatures of ca. 70 °C were assigned to the thermodynamically favoured recovery of the supramolecular gel.

Polymer-supported ionic-liquid-like phases (SILLPs): transferring ionic liquid properties to polymeric matrices.

The physico-chemical properties of polymers with ionic-liquid-like moieties covalently bound to their surfaces (SILLPs) have been studied by thermal and spectroscopic techniques, as well as by direct impedance and dielectric measurements, and compared to those of the corresponding bulk ionic liquids. The effective transfer of properties from ionic liquids in solution to the supported species has thereby been demonstrated. The effects of the chemical nature of these tunable "solid solvents" on their macroscopic swelling and microwave heating, as well as the stabilities and activities of different catalytic moieties immobilized on the SILLPs, have been studied. Finally, the experimental effect observed in microwave heating can be directly correlated with the values of tan δ derived from dielectric measurements.