Impact of Microwaves on Organic Synthesis and Strategies toward Flow Processes and Scaling Up.

Microwave-assisted organic synthesis has been widely studied and deliberated, opening up some controversial issues as well. Nowadays, microwave chemistry is a mature technology that has been well demonstrated in many cases with numerous advantages in terms of the reaction rate and yield. The strategies toward scaling up find an ally in continuous-flow reactor technology comparing dielectric and conductive heating.

Cyclodextrins in the antiviral therapy.

The main antiviral drug-cyclodextrin interactions, changes in physicochemical and physiological properties of the most commonly used virucides are summarized. The potential complexation of antiviral molecules against the SARS-Cov2 also pointed out the lack of detailed information in designing effective and general medicines against viral infections. The principal problem of the current molecules is the 3D structures of the currently active compounds. Improving the solubility or bioavailability of antiviral molecules is possible, however, there is no universal solution, and the complexation experiments dominantly use the already approved cyclodextrin derivatives. This review discusses the basic properties of the different cyclodextrin derivatives, their potential in antiviral formulations, and the prevention and treatment of viral infections. The biologically active new cyclodextrin derivatives are also discussed.

Microwave Irradiation in Micro- Meso-Fluidic Systems; Hybrid Technology has Issued the Challenge.

A combination of microwave irradiation and flow chemistry has been described as a promising smart and hyphenated technology that can fuse and synergize the benefits of the techniques. The cells and tissues of all living organisms promote a huge number of bioorganic reactions that occur as flow systems and not the batch-type conditions typically used by chemists and biotechnologists. Microwave-assisted chemical conversion carried out in continuous flow mode with micro- or meso-channel reactors can offer significant processing advantages, including improved thermal exchange, energy efficiency, safety, mixing control, a wider range of reaction conditions, repeatability and scalability as well as dramatic reductions in side-reactions and degradations. This review will discuss relevant examples of organic synthesis and nanoparticles production performed in continuous flow mode with integrated microwave irradiation in micro- or mesofluidic systems.

Sonochemically-Promoted Preparation of Silica-Anchored Cyclodextrin Derivatives for Efficient Copper Catalysis.

Silica-supported metallic species have emerged as valuable green-chemistry catalysts because their high efficiency enables a wide range of applications, even at industrial scales. As a consequence, the preparation of these systems needs to be finely controlled in order to achieve the desired activity. The present work presents a detailed investigation of an ultrasound-promoted synthetic protocol for the grafting of ß-cyclodextrin (ß-CD) onto silica. Truly, ultrasound irradiation has emerged as a fast technique for promoting efficient derivatization of a silica surface with organic moieties at low temperature. Three different ß-CD silica-grafted derivatives have been obtained, and the ability of ß-CD to direct and bind Cu when CD is bonded to silica has been studied. A detailed characterization has been performed using TGA, phenolphthalein titration, FT-IR, diffuse reflectance (DR), DR UV-Vis, as well as the inductively-coupled plasma (ICP) of the ß-CD silica-grafted systems and the relative Cu-supported catalysts. Spectroscopic characterization monitored the different steps of the reaction, highlighting qualitative differences in the properties of amino-derivatized precursors and final products. In order to ensure that the Cu-ß-CD silica catalyst is efficient and robust, its applicability in Cu(II)-catalyzed alkyne azide reactions in the absence of a reducing agent has been explored. The presence of ß-CD and an amino spacer has been shown to be crucial for the reactivity of Cu(II), when supported.

Reaction of oxiranes with cyclodextrins under high-energy ball-milling conditions.

This work presents a proof of concept for a green cyclodextrin derivatisation method that uses low-boiling epoxide reagents in a high-energy ball mill (HEBM). The simplified preparation and purification of low substitution-degree common (2-hydroxy)propylated ß- and γ-cyclodextrins (ß/γ-CDs) has been realised. The intelligent use of propylene oxide has also facilitated the more effective synthesis of highly substituted γ-CD. Epichlorohydrin-crosslinked CD-polymers (CDPs) have also been effectively prepared in the ball mill. The unoptimised preparations of soluble and insoluble CDPs displayed very small particle size distributions, while the prepared polymers currently have different complexation properties to those of their classically prepared analogues.

Microwave-Assisted Synthesis and Physicochemical Characterization of Tetrafuranylporphyrin-Grafted Reduced-Graphene Oxide.

This work describes the design of a modified porphyrin that bears four furan rings linked by 1,2-bis-(2-aminoethoxy)ethane spacers. This unit is a well-suited scaffold for a Diels-Alder reaction with commercial reduced-graphene oxide, which is also described in this paper. A new hybrid material is obtained, thanks to efficient grafting under microwave irradiation, and fully characterized in terms of structure (UV, TGA, Raman) and morphology (HR-TEM and AFM). Potential applications in photo- and sonodynamic therapy are envisaged.

Enabling technologies and green processes in cyclodextrin chemistry.

The design of efficient synthetic green strategies for the selective modification of cyclodextrins (CDs) is still a challenging task. Outstanding results have been achieved in recent years by means of so-called enabling technologies, such as microwaves, ultrasound and ball mills, that have become irreplaceable tools in the synthesis of CD derivatives. Several examples of sonochemical selective modification of native α-, ß- and γ-CDs have been reported including heterogeneous phase Pd- and Cu-catalysed hydrogenations and couplings. Microwave irradiation has emerged as the technique of choice for the production of highly substituted CD derivatives, CD grafted materials and polymers. Mechanochemical methods have successfully furnished greener, solvent-free syntheses and efficient complexation, while flow microreactors may well improve the repeatability and optimization of critical synthetic protocols.

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins.

A number of per-6-substituted cyclodextrin derivative syntheses have been effectively carried out in a planetary ball mill under solvent-free conditions. The preparation of Bridion® and important per-6-amino/thiocyclodextrin intermediates without polar aprotic solvents, a source of byproducts and persistent impurities, could be performed. Isolation and purification processes could also be simplified. Considerably lower alkylthiol/halide ratio were necessary to reach the complete reaction in comparison with thiourea or azide reactions. While the presented mechanochemical syntheses were carried out on the millimolar scale, they are easily scalable.

Interplay Between Mechanochemistry and Sonochemistry.

Ultrasonic irradiation-based mechanochemical strategies have recently been the subject of intensive investigation because of the advantages they offer. These include simplicity, energy savings and wide applicability. Traditional areas of sonoprocessing such as cleaning, efficient mixing and solid activation have been extended to both macromolecular and micro/nanostructures, some of which are biologically significant, ultrasound-responsive actuators and crystal design, among others. Unlike conventional mechanochemical protocols, which require little solvent usage if any at all, mechanical (and chemical) effects promoted by ultrasound are observed in a liquid medium. Tensile forces, which share similarities with solid mechanochemistry, are generated by virtue of nonlinear effects, notably cavitation, when high-amplitude waves propagate in a fluid. This work aims to provide insight into some recent developments in the multifaceted field of sono-mechanochemistry using various examples that illustrate the role of ultrasonic activation, which is capable of boosting hitherto sterile transformations and inventing new crafts in applied chemistry. After a preliminary discussion of acoustics, which is intended to provide a mechanistic background, we mainly focus on experimental developments, while we often mention emerging science and occasionally delve into theoretical models and force simulations.

Complexes of peracetylated cyclodextrin in a non-aqueous aprotic medium: the role of residual water.

This paper describes the interaction between aromatic esters and peracetylated cyclodextrins (CDs) studied by NMR spectroscopy in deuterochloroform (CDCl3). The observed chemical shift changes highlight the existence of interactions between an aromatic alkyl ester, water and peracetylated CDs. In some cases, substituent chemical shift determination was influenced by the low water content of CDCl3 and/or the host molecule. Higher CD concentrations resulted in water signal drifts in all studied cases. It was not possible to obtain a completely dry sample of peracetyl γCD: ∼1 mol of water remained and the water signal showed reversed movement, with respect to the other two CD analogues, upon increasing host concentration. The estimated 1 : 1 stability constants for the water : peracetyl CD complexes are in the 50-150 M(-1) range in CDCl3, but show a relatively large calculation error. The calculated 1 : 1 stability constants for the peracetyl CD : ester complexes are also in this range, but 1 : 2 and 2 : 1 complex compositions are also possible. Overall, our results highlight dynamic aspects of water nanoconfined in a highly hydrophobic environment, thus mimicking biological recognition where a few water molecules often play a pivotal role.

Solvent-free copper-catalyzed azide-alkyne cycloaddition under mechanochemical activation.

The ball-mill-based mechanochemical activation of metallic copper powder facilitates solvent-free alkyne-azide click reactions (CuAAC). All parameters that affect reaction rate (i.e., milling time, revolutions/min, size and milling ball number) have been optimized. This new, efficient, facile and eco-friendly procedure has been tested on a number of different substrates and in all cases afforded the corresponding 1,4-disubstituted 1,2,3-triazole derivatives in high yields and purities. The final compounds were isolated in almost quantitative overall yields after simple filtration, making this procedure facile and rapid. The optimized CuAAC protocol was efficiently applied even with bulky functionalized ß-cyclodextrins (ß-CD) and scaled-up to 10 g of isolated product.

Pd/C-catalyzed aerobic oxidative esterification of alcohols and aldehydes: a highly efficient microwave-assisted green protocol.

We herein describe an environmentally friendly microwave-assisted oxidative esterification of alcohols and aldehydes in the presence of molecular oxygen and a heterogeneous catalysis (Pd/C, 5 mol %). This efficient and ligandless conversion procedure does not require the addition of an organic hydrogen acceptor. The reaction rate is strongly enhanced by mild dielectric heating. Furthermore, it is a versatile green procedure which generally enables the isolation of esters to be carried out by simple filtration in almost quantitative yields.

Copper-Catalyzed Continuous-Flow Transfer Hydrogenation of Nitroarenes to Anilines: A Scalable and Reliable Protocol.

A robust supported catalyst that is made up of copper nanoparticles on Celite has been successfully prepared for the selective transfer hydrogenation of aromatic nitrobenzenes to anilines under continuous flow. The method is efficient and environmentally benign thanks to the absence of hydrogen gas and precious metals. Long-term stability studies show that the catalytic system is able to achieve very high nitrobenzene conversion (>99%) when working for up to 145 h. The versatility of the transfer hydrogenation system has been tested using representative examples of nitroarenes, with moderate-to-excellent yields being obtained. The packed bed reactor (PBR) permits the use of a setup that can provide products via simple isolation by SPE without the need for further purification. The recovery and reuse of either EG or the ion-exchange resin leads to consistent waste reduction; therefore, E-factor distribution analysis has highlighted the environmental efficiency of this synthetic protocol.

Design and Synthesis of a γ(1)ß(8)-Cyclodextrin Oligomer: A New Platform with Potential Application as a Dendrimeric Multicarrier.

We report the synthesis and characterization of a water-soluble, star-shaped macromolecular platform consisting of eight ß-cyclodextrin (ß-CD) units anchored to the narrower rim of a γ-CD core through bis(triazolyl)alkyl spacers. The efficient synthetic protocol is based on the microwave (MW)-promoted Cu-catalyzed 1,3-dipolar cycloaddition of CD monoazides to CD monoacetylenes. The ligand-hosting capability of the construct has been assessed by relaxometric titration and nuclear magnetic relaxation dispersion (NMRD) profiling, which showed it to be good, and this was supported by molecular dynamics simulations. To demonstrate the feasibility of obtaining supramolecular structures with high hosting ability, we designed a dimeric platform, formed by joining two nonamers through the γ-CD cores through a bis(lithocholic acid) linker. With a view to the potential biological applications, cytotoxicity and extent of binding to human serum albumin were assessed. The properties of this dendrimeric multicarrier make it suitable for pharmaceutical and diagnostic purposes, ranging from targeted drug delivery to molecular imaging.

One-pot sequential synthesis of isocyanates and urea derivatives via a microwave-assisted Staudinger-aza-Wittig reaction.

A fast and efficient protocol for the synthesis of N,N'-disubstituted urea derivatives from alkyl halides and primary or secondary amines has been developed. The synthetic pathway combines nucleophilic substitutions and a Staudinger-aza-Wittig reaction in the presence of polymer-bound diphenylphosphine under 14 bar of CO2 pressure and has been performed in a one-pot two-step process. The protocol has been optimized under microwave irradiation and the scale-up experiment has been conducted under conventional conditions in a Parr reactor. The final compounds were isolated after simple filtration in almost quantitative overall yields which makes this procedure facile and rapid to execute.

Diterpenes stability of commercial blends of roasted and ground coffees packed in copolymer coupled with aluminium and eco-friendly capsules.

Diterpenes are group of compounds of the terpenic fraction of roasted coffee and account for about 7-20 % (w/w) of the lipid fraction. Several parameters can influence their occurrence in coffee beans and beverages including species and post-harvest processing. Diterpenes in coffee have been studied extensively, but to the best of the authors' knowledge, there is no information in the literature on their stability over time. Coffee is a relatively stable product under optimal temperature, humidity and oxygen conditions. However, during storage it can undergo a series of chemical and physical reactions that alter its flavour and lead to rancidity, mainly due to the oxidative reactions that take place on the lipid fraction. In this study, the effect of long-term storage on the diterpene content of different commercial coffee blends and packaging is analysed and critically discussed. The Results show that the storage influences the internal environment of the capsules with an increase in moisture and a decrease in pH favouring more reactive conditions, especially for Eco capsules. Relative stability over time is observed for cafestol and kahweol. dehydro derivatives show a degradation up to T60 independently on the blends and packaging, which is not related to their precursors. The permeability of packaging and blends affect the modification of these components: while a drastic oxidation process takes place in Arabica eco compatible capsules (PC) when acidity and moisture increase, in Arabica/Robusta eco compatible capsules (IC) as well as in Arabica/Robusta and Arabica standard capsules (IS and PS) the peroxides tend to increase resulting in an autocatalytic propagation.

Surface Functionalised Parenteral Nanoemulsions for Active and Homotypic Targeting to Melanoma.

Despite recent progressions in cancer genomic and immunotherapies, advanced melanoma still represents a life threat, pushing to optimise new targeted nanotechnology approaches for specific drug delivery to the tumour. To this aim, owing to their biocompatibility and favourable technological features, injectable lipid nanoemulsions were functionalised with proteins owing to two alternative approaches: transferrin was chemically grafted for active targeting, while cancer cell membrane fragments wrapping was used for homotypic targeting. In both cases, protein functionalisation was successfully achieved. Targeting efficiency was preliminarily evaluated using flow cytometry internalisation studies in two-dimensional cellular models, after fluorescence labelling of formulations with 6-coumarin. The uptake of cell-membrane-fragment-wrapped nanoemulsions was higher compared to uncoated nanoemulsions. Instead, the effect of transferrin grafting was less evident in serum-enriched medium, since such ligand probably undergoes competition with the endogenous protein. Moreover, a more pronounced internalisation was achieved when a pegylated heterodimer was employed for conjugation (p < 0.05).

Determination of trace antibiotics in water and milk via preconcentration and cleanup using activated carbons.

CPAC-SPE-HPLC (coconut powdered activated carbon -SPE- HPLC) has been developed for the determination of antibiotic (ABX), sulfamonomethoxine sodium (SMM), oxytetracycline (OTC), ceftiofur hydrochloride (CEF) and marbofloxacin (MAR), in water and milk. Over 99.0% SMM and OTC were recovered from 20 mL of 0.5 µg/mL ABX solution using 10 mg-CPAC for adsorption and 2 mL of 30% NH4OH/EtOH (1/19 v/v) for elution. Similarly, over 99.0% CEF and MAR were recovered using 15 mg-CPAC and 2 mL of 30% NH4OH/n-PrOH (1/19 v/v). Moreover, the recovery efficiencies of various ABX from 5 to 80 mL of 0.02-2.00 µg/mL medicated milk containing 10 mM EDTA are ordered as follows: OTC (99.3%), SMM (99.1%) > CEF (68.9%) > MAR (61.4%). No interference towards HPLC analysis were observed with elution using 2 mL of 30% NH4OH/EtOH (1/19 v/v). Furthermore, much lower limit of detections (0.02 µg/mL) than the maximum residual limits from European Commission (0.075-0.100 µg/mL) were obtained.

Glycerol: An Optimal Hydrogen Source for Microwave-Promoted Cu-Catalyzed Transfer Hydrogenation of Nitrobenzene to Aniline.

The search for sustainable alternatives for use in chemical synthesis and catalysis has found an ally in non-conventional energy sources and widely available green solvents. The use of glycerol, an abundant natural solvent, as an excellent "sacrificial" hydrogen source for the copper-catalyzed microwave (MW)-promoted transfer hydrogenation of nitrobenzene to aniline has been investigated in this work. Copper nanoparticles (CuNPs) were prepared in glycerol and the efficacy of the glycerol layer in mediating the interaction between the metal active sites has been examined using HRTEM analyses. Its high polarity, low vapor pressure, long relaxation time, and high acoustic impedance mean that excellent results were also obtained when the reaction media was subjected to ultrasound (US) and MW irradiation. US has been shown to play an important role in the process via its ability to enhance CuNPs dispersion, favor mechanical depassivation and increase catalytic active surface area, while MW irradiation shortened the reaction time from some hours to a few minutes. These synergistic combinations promoted the exhaustive reduction of nitrobenzene to aniline and facilitated the scale-up of the protocol for its optimized use in industrial MW reactors.

Nanoemulsions as Delivery Systems for Poly-Chemotherapy Aiming at Melanoma Treatment.

Aims: Advanced melanoma is characterized by poor outcome. Despite the number of treatments having been increased over the last decade, current pharmacological strategies are only partially effective. Therefore, the improvement of the current systemic therapy is worthy of investigation. Methods: a nanotechnology-based poly-chemotherapy was tested at preclinical level. Temozolomide, rapamycin, and bevacizumab were co-loaded as injectable nanoemulsions for total parenteral nutrition (Intralipid®), due to suitable devices, and preliminarily tested in vitro on human and mouse cell models and in vivo on the B16-F10 melanoma mouse model. Results: Drug combination was efficiently loaded in the liquid lipid matrix of Intralipid®, including bevacizumab monoclonal antibody, leading to a fast internalization in tumour cells. An increased cytotoxicity towards melanoma cells, as well as an improved inhibition of tumour relapse, migration, and angiogenesis were demonstrated in cell models for the Intralipid®-loaded drug combinations. In preliminary in vivo studies, the proposed approach was able to reduce tumour growth significantly, compared to controls. A relevant efficacy towards tumour angiogenesis and mitotic index was determined and immune response was involved. Conclusions: In these preliminary studies, Intralipid® proved to be a safe and versatile poly-chemotherapy delivery system for advanced melanoma treatment, by acting on multiple mechanisms.