2-Methyloxolane as an effective bio-based solvent for the removal of ßN-alkanoyl-5-hydroxytryptamines from Arabica green coffee beans.

ßN-alkanoyl-5-hydroxytryptamines (Cn-5HTs) are the main constituents of coffee wax and may be responsible for the increased severity of gastric disorders in sensitive consumers. Their removal from green coffee beans can result in a "stomach-friendly" brew. This work presents a green approach to Cn-5HTs extraction using the bio-based solvent 2-methyloxolane (2-MeOx). HPLC/DAD analyses on Arabica Brazil samples show that mild conditions (30 min at 50 °C) extract about 90% of the wax, without affecting the caffeine content of the beans, whereas almost complete removal is achieved in 60 min at reflux. 2-MeOx forms an azeotrope with water, its possible re-use has been demonstrated using aqueous 2-MeOx (95.5%) as the solvent. These preliminary results make 2-MeOx a possible candidate for the replacement of dichloromethane (DCM) in coffee dewaxing. The importance of fermentation in reducing Cn-5HTs by about 36% has been demonstrated in an analysis of green beans subjected to different post-harvest treatments.

From Batch to the Semi-Continuous Flow Hydrogenation of pNB, pNZ-Protected Meropenem.

Meropenem is currently the most common carbapenem in clinical applications. Industrially, the final synthetic step is characterized by a heterogeneous catalytic hydrogenation in batch mode with hydrogen and Pd/C. The required high-quality standard is very difficult to meet and specific conditions are required to remove both protecting groups [i.e., p-nitrobenzyl (pNB) and p-nitrobenzyloxycarbonyl (pNZ)] simultaneously. The three-phase gas-liquid-solid system makes this step difficult and unsafe. The introduction of new technologies for small-molecule synthesis in recent years has opened up new landscapes in process chemistry. In this context, we have investigated meropenem hydrogenolysis using microwave (MW)-assisted flow chemistry for use as a new technology with industrial prospects. The reaction parameters (catalyst amount, T, P, residence time, flow rate) in the move from the batch process to semi-continuous flow were investigated under mild conditions to determine their influence on the reaction rate. The optimization of the residence time (840 s) and the number of cycles (4) allowed us to develop a novel protocol that halves the reaction time compared to batch production (14 min vs. 30 min) while maintaining the same product quality. The increase in productivity using this semi-continuous flow technique compensates for the slightly lower yield (70% vs. 74%) obtained in batch mode.

Towards Antibiotic Synthesis in Continuous-Flow Processes.

Continuous-flow chemistry has become a mainstream process and a notable trend among emerging technologies for drug synthesis. It is routinely used in academic and industrial laboratories to generate a wide variety of molecules and building blocks. The advantages it provides, in terms of safety, speed, cost efficiency and small-equipment footprint compared to analog batch processes, have been known for some time. What has become even more important in recent years is its compliance with the quality objectives that are required by drug-development protocols that integrate inline analysis and purification tools. There can be no doubt that worldwide government agencies have strongly encouraged the study and implementation of this innovative, sustainable and environmentally friendly technology. In this brief review, we list and evaluate the development and applications of continuous-flow processes for antibiotic synthesis. This work spans the period of 2012-2022 and highlights the main cases in which either active ingredients or their intermediates were produced under continuous flow. We hope that this manuscript will provide an overview of the field and a starting point for a deeper understanding of the impact of flow chemistry on the broad panorama of antibiotic synthesis.

The challenge of o-phenylphenol detection in coffee: How "OPP-conjugates" hide their presence in green and roasted samples.

o-Phenylphenol (OPP) is not a commonly used pesticide in the coffee production chain. Although it has only been detected in roasted coffee, it is unlikely that OPP can be formed during roasting. Its acidic nature may lead to the formation of conjugates with natural matrix components. The objective of this study is to optimize an analytical method to discover how these conjugates may mask the presence of OPP in coffee. Sample extraction with hexane followed by basic hydrolysis and then a QuEChERS method allows the presence of OPP to be quantitatively detected via UPLC-MS/MS. The optimized method was applied to the same Arabica coffee (Brazil), and the quantification of comparable amounts of OPP was observed in both green and roasted samples (34.8 vs 32.2 µg/kg). The optimized procedure detected twice the amount of OPP in roasted samples, compared to the QuEChERS method, suggesting that roasting causes the partial hydrolysis of OPP conjugates.

Cefonicid Benzathine Salt: A Convenient, Lean, and High-Performance Protocol to Make an Old Cephalosporin Shine.

Cefonicid is a second-generation cephalosporin sold under the brand name Sintocef™. It is an injectable drug obtained via a freeze-drying process and is also available for oral preparations. The high-quality standard required is very challenging to satisfy, and current production protocols are characterized by steps that are lengthy and cumbersome, making the product unattractive for the international market. Industrial R&D is constantly working on the process optimization for API synthesis, with the aim of increasing productivity and decreasing production costs and waste. We herein report a new and efficient method for the synthesis of the cefonicid benzathine salt that provides a good yield and high product stability. The double-nucleophilic and lipophilic nature of N',N″-dibenzylethylene diacetate enables the deformylation of the OH-protected group on the mandelic moiety and also enables product crystallization to occur. We demonstrate that the formyl group in the peculiar position has high reactivity, promoting an amidation reaction that deprotects a hydroxy group and generates a new C-N bond in the reaction by-product. Several amines and OH-protected groups have been studied, but none were able to replicate the excellent results of benzathine diacetate.

Microwave-Assisted, One-Pot Synthesis of Doxycycline under Heterogeneous Catalysis in Water.

The selective synthesis of active pharmaceutical molecules is a challenging issue, particularly when attempting to make the reactions even more sustainable. The present work focuses on the microwave-assisted hydrogenolysis of oxytetracycline to selectively produce α-doxycycline. Although the combination of microwave irradiation and a heterogeneous rhodium catalyst provided good conversions, the selective synthesis of active α-doxycycline was only achieved when an oxytetracycline-cyclodextrin complex was used as the starting material, giving the desired product at 34.0% yield in a one-step reaction under very mild conditions.

Phthalimide Residue in Coffee: Does It Solely Derive from Folpet?

Folpet, a fungicide used on several crops, easily degrades into phthalimide (PAI) at high temperatures and basic pH. The maximum admitted limit for Folpet in foodstuffs as coffee is defined by the sum of its amount and that of PAI. Noteworthy, PAI can also arise from the reaction between ubiquitous phthalate derivatives and NH3. This work aims to demonstrate that the detection of PAI in roasted coffee is not necessarily diagnostic for Folpet as it can also originate from the reaction between phthalic anhydride (PAA), derived from phthalates, and amino acids (AAs), as a NH3 source. Thermal treatment of AAs with PAA confirmed that PAI generation follows a temperature-dependent path. Experiments with diethyl phthalate (DEP) and AAs have shown that maximum PAI generation via heating occurs at 200 °C for 60 min. PAI generation has also been proven for Folpet-free green coffee beans that were heated under laboratory and industrial roasting conditions.

Polycyclic aromatic hydrocarbons in coffee samples: Enquiry into processes and analytical methods.

Polycyclic aromatic hydrocarbons (PAHs) are considered to be potentially genotoxic and carcinogenic in humans. These ubiquitous environmental pollutants may derive from the incomplete combustion and pyrolysis of organic matter. Coffee is an extensively consumed drink, and its PAHs contamination is not only ascribed to environmental pollution, but mainly to the roasting processes. Although no fixed limits have yet been set for residual PAHs in coffee, the present review intends to summarise and discuss the knowledge and recent advances in PAHs formation during roasting. Because coffee origin and brewing operations may affect PAHs content, we thoroughly analysed the literature on extraction and purification procedures, as well as the main analytical chromatographic methods for both coffee powders and brews. With regards to the safety of this appreciated commodity, the control on the entire production chain is desirable, because of coffee beverage could contribute to the daily human intake of PAHs.

Green Enabling Technologies for Competitive Synthesis of Pharmaceutical Lead Compounds.

Combinations of different technologies are at the heart of the development and implementation of new, innovative processes and approaches for Industry 4.0 in the field of medicinal chemistry and drug discovery. Process intensification and advances in high-throughput synthetic techniques can dramatically improve reaction rates in processes for which slow kinetics represents a bottleneck. Easier access to target-based chemical library collections offers wider access to new leads for drug development. Green enabling technologies are a reliable ally for the design of environmentally friendly synthetic processes and more highly competitive pharmaceutical production. Mechanochemistry, microwaves, ultrasound and flow chemistry are mature techniques that can boast drug synthesis when properly integrated into the production chain. In this review, we selected examples from the literature of the last five years related to medicinal chemistry.

Ozonated Oils as Antimicrobial Systems in Topical Applications. Their Characterization, Current Applications, and Advances in Improved Delivery Techniques.

The search for a wide spectrum of antimicrobial agents that can avoid resistance while maintaining reasonable side effects has led to ozonated oils experiencing an increase in scientific interest and clinical applications. The treatment of vegetable oils with ozone leads to the creation of a reservoir of ozone that slowly releases into the skin thanks to the fact that ozone can be held as ozonides of unsaturated fatty acids. Interest in the use of ozonated oils has meant that several ozonated-vegetable-oil-containing products have been commercialized as cosmetic and pharmaceutical agents, and in innovative textile products with antibacterial activity. New approaches to the delivery of ozonated oils have very recently appeared in an attempt to improve their characteristics and reduce drawbacks, such as an unpleasant odor, high viscosity and undesired effects on skin, including irritation and rashes. The present review focuses on the current status of delivery agents that use ozonated oils as antimicrobial agents in topical (dermal, skin, and soft tissues) treatments. Challenges and future opportunities for these delivery systems will also be discussed.

SWCNT-porphyrin nano-hybrids selectively activated by ultrasound: an interesting model for sonodynamic applications.

Sonodynamic therapy (SDT) is an innovative anticancer approach, based on the excitation of a given molecule (usually a porphyrin) by inertial acoustic cavitation that leads to cell death via the production of reactive oxygen species (ROS). This study aims to prepare and characterize nanosystems based on porphyrin grafted carbon nanotubes (SWCNTs), to understand some aspects of the mechanisms behind the SDT phenomenon. Three different porphyrins have been covalently linked to SWCNTs using either Diels-Alder or 1,3-dipolar cycloadditions. ROS production and cell viability have been evaluated upon ultrasound irradiation. Despite the low porphyrin content linked on the SWCNT, these systems have shown high ROS production and high tumour-cell-killing ability. The existence of a PET (photoinduced electron transfer)-like process would appear to be able to explain these observations. Moreover, the demonstrated ability to absorb light limits the impact of side effects due to light-excitation.

Green Protocols in Heterocycle Syntheses via 1,3-Dipolar Cycloadditions.

The aim of this review is to provide an overview of green protocols for the organic synthesis of heterocycles via 1,3-dipolar cycloaddition. Particular attention has been devoted to the use of green solvents; reactions performed in ionic liquids, fluorinated solvents and water have been included. Also explored are several protocols that make use of catalyst-free reaction conditions, the use of microwave irradiation and activation by light exposure. Improvements over commonly used organic solvents will be underlined in order to highlight environmental protection aspects and enhancements in regio- and stereo-selectivity.

Harnessing cavitational effects for green process intensification.

The impressive chemico-physical effects observed in sonochemistry are a result of cavitation, as ultrasonic and hydrodynamic cavitation does not interact with matter at the atomic and molecular levels. Bubble collapse leads to the quasi-adiabatic heating of the vapour inside bubbles, giving rise to local hot spots in the fluid. Cavitation thus transforms a mechanical energy into high kinetic energy, which is released in very short bursts that are exploited for green process intensification. This paper reviews relevant applications of hydrodynamic and acoustic cavitation with the aim of highlighting the particular advantages that these phenomena offer to the intensification of green chemical processes. Emulsification, biodiesel preparation, wastewater decontamination, organic synthesis, enzymatic catalysis and extractions are discussed among others. As a comparison, hydrodynamic cavitation technique is more advantageous in dealing with process intensification at large-scale, as well as the enhancement of mass transfer and heat transfer, while ultrasonic cavitation technique is more convenient to operate, easier to control in the studies at lab-scale, and exhibits more efficient in producing active free radicals and inducing the cleavage of volatile compounds.

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.

Combined Microwaves/Ultrasound, a Hybrid Technology.

The combination of microwave heating and ultrasound irradiation has been successfully exploited in applied chemistry. Besides saving energy, these green techniques promote faster and more selective transformations. The aim of this review is to provide a practical overview of the complimentary and synergistic effects generated by the combination of microwaves and either ultrasound or hydrodynamic cavitation. This will begin with a brief history, as we outline pioneering achievements, and will also update the reader on recent developments. Such hyphenated techniques are able to offer reliable and efficient protocols for basic chemistry, organic and inorganic synthesis as well as processing. The development of dedicated hybrid reactors has helped scientists to find solutions to new synthetic challenges in the preparation of nanomaterials and new green catalysts. This research topic falls within the confines of process intensification as it facilitates the design of substantially cleaner, safer and more energy efficient technologies and chemical processes.

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 built on a sonochemical platform: challenges and opportunities.

Scientific and technological progress now occurs at the interface between two or more scientific and technical disciplines while chemistry is intertwined with almost all scientific domains. Complementary and synergistic effects have been found in the overlay between sonochemistry and other enabling technologies such as mechanochemistry, microwave chemistry and flow-chemistry. Although their nature and effects are intrinsically different, these techniques share the ability to significantly activate most chemical processes and peculiar phenomena. These studies offer a comprehensive overview of sonochemistry, provide a better understanding of correlated phenomena (mechanochemical effects, hot spots, etc.), and pave the way for emerging applications which unite hybrid reactors.

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.

Ultrasound-enhanced one-pot synthesis of 3-(Het)arylmethyl-4-hydroxycoumarins in water.

3-(Aryl)methyl-4-hydroxycoumarins were produced in good to excellent yields by reaction between 4-hydroxycoumarin and (hetero)aromatic aldehydes in the presence of Hantzsch 1,4-dihydropyridine (HEH) which works as an hydride donor (i.e., in a sequential Knoevenagel-reductive Michael addition). The sonochemical-assisted procedure (method B) provides an improved and accelerated conversion when compared to conventional silent reactions (method A). Experiments carried out according to method B showed that the reaction could be more efficiently run in the absence of organic solvents, at 30-40°C in open vessel, without the need of an excess HEH and with simplified work-up and separation procedures.

Alkyne-azide click reaction catalyzed by metallic copper under ultrasound.

This protocol is for the ultrasound (US)-assisted 1,3-dipolar cycloaddition reaction of azides and alkynes using metallic copper (Cu) as the catalyst. The azido group is a willing participant in this kind of organic reaction and its coupling with alkynes is substantially improved in the presence of Cu(I). This protocol does not require additional ligands and proceeds with excellent yields. The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) is generally recognized as the most striking example of 'click chemistry'. Reactions involving metals represent the favorite domain of sonochemistry because US favors mechanical depassivation and enhances both mass transfer and electron transfer from the metal to the organic acceptor. The reaction rate increases still further when simultaneous US and microwave irradiation are applied. The US-assisted click synthesis has been applied for the preparation of a wide range of 1,4-disubstituted 1,2,3-triazole derivatives starting both from small molecules and oligomers such as cyclodextrins (CDs). Using this efficient and greener protocol, all the adducts can be synthesized in 2-4 h (including work-up and excluding characterization). Click chemistry has been shown to be able to directly link chemistry to biology, thus becoming a true interdisciplinary reaction with extremely wide applicability.