Reaction Mass Efficiency Research Articles

Sustainable Chemistry in Synthesis of Heterocyclic Systems: [Atom Economy, Yield Economy and Reaction Mass Efficiency As Metrics of Synthetic Reaction Efficiency

Sustainable Chemistry in Synthesis of Heterocyclic Systems: [Atom Economy, Yield Economy and Reaction Mass Efficiency As Metrics of Synthetic Reaction Efficiency

Synthesis of Pyrrolo [2,1-a]isoquinolines using Cu NPs decorated microcrystalline cellulose in 2-Methyl-THF: A biodegradable heteregeneous nanocatalyst for the sustainable cascade approach

Copper nanoparticles (Cu NPs) supported on microcrystalline cellulose (MCC) serve as an efficient and biodegradable heterogeneous nanocatalyst for the synthesis of pyrrolo [1,2a] isoquinoline under mild and sustainable reaction conditions through a cascade reaction involving condensation, addition, oxidation, and cyclization events. The catalyst underwent thorough characterization via various techniques, including FT-IR, PXRD, XPS, FE-SEM, EDX, TEM, and HR-TEM analysis. Optimized reaction conditions facilitated high-yield production of a diverse range of pyrrolo [1,2a] isoquinolines in 2-Me THF solvent, and the method demonstrated scalability with successful gram-scale synthesis. Notably, the catalyst exhibited reusability for up to five cycles without a significant decrease in activity. This approach aligns with eco-friendly principles, as evidenced by favorable green chemistry metrics for compound 4a, including low process mass intensity (7.83), a minimal environmental impact factor (6.83), a substantial atom economy (67.56 %), efficient reaction mass efficiency (60.76 %), high chemical yield (92.37 %), low mass intensity (1.64), notable mass productivity (60.97 %), considerable carbon efficiency (69.15 %), and optimum efficiency (89.93 %). These results highlight the sustainable and environmentally conscious nature of the developed synthetic methodology.

Application of Fe3O4@MCC Nanoparticles as a Heterogeneous Catalyst for Sustainable Multicomponent Synthesis of 2,3′‐Biindoles

AbstractDeveloping innovative methods for synthesizing unique 2,3'‐biindole derivatives is crucial for the progression of drug and material discovery. The use of transition‐metal‐catalyzed coupling improves the efficiency and structural diversity in the synthesis of biindoles. Among these methods, heterogeneous catalysis, particularly using Fe3O4 nanocatalyst supported by microcrystalline cellulose (MCC), is promising for green chemistry applications. In the present work, sixteen 2,3'‐biindole derivatives (4a‐p) were prepared using Fe3O4@MCC nanocatalyst which demonstrated enhanced performance, cost‐effectiveness, and reusability. The magnetic properties of the catalyst enable easy separation, simplifying purification processes, and enhancing overall reaction efficiency to 78%–93%. This method aligns with sustainable chemical practices and offers practical benefits for various industrial applications. This environment friendly method boasts several advantages and demonstrates excellent green chemistry metrics, including process mass intensity, environmental impact factor, atom economy, and reaction mass efficiency, atom economy, carbon efficiency, chemical yield, and optimum efficiency.

Sustainable Synthesis of D‐Glucose Based IL: A Renewable Organo Catalyst for the Efficient Synthesis of Dihydropyrano Coumarins

A convenient, direct, one‐pot highly efficient microwave‐assisted synthesis of biomass‐derived D‐glucose‐based hydroxide ionic liquid via a simple three‐step approach has been described. The key features of the method include rapidness, eco‐friendliness, and excellent yields. To the best of our knowledge, this is the first methodology for synthesizing D‐Glucose‐based sugar ionic liquid (GSIL) under microwave irradiation. The developed catalyst allowed us to synthesize diverse dihydropyrano[3,2‐c]‐chromenes upto 95% yield in 30‐90 min stirring at 80 ̊C under mild conditions. The scope of the study was investigated using 30 instances. Developed GSILs exhibited excellent catalytic activity as well as good recyclability. Overall, the catalyst showed excellent value in green chemistry parameters such as atom economy (95%), E‐factor (0.05), carbon efficiency (100%), process mass intensity (1.62), and reaction mass efficiency (0.860).

Effectiveness of Xanthan Gum-based composite in repairing cracks in reinforced concrete structures

Abstract This study investigates the enhancement of concrete slabs using a biopolymer-modified cementitious repair material (CXT) composed of Ordinary Portland Cement, Xanthan Gum, and Tartaric Acid Powder. The innovative formulation of CXT aims to improve the mechanical properties of repaired concrete structures. Experimental results demonstrate that CXT significantly enhances mechanical properties such as the load-bearing capacity of concrete slabs. Non-destructive testing methods, including the Rebound Hammer test and Ultrasonic Pulse Velocity (UPV), as well as destructive testing methods, were employed to evaluate the performance of CXT in repairing cracks. The study highlights the improved load-bearing capacity and structural integrity of CXT-repaired slabs, contributing to increased longevity and reduced maintenance costs of concrete structures. Furthermore, the sustainability metrics of CXT, including Process Mass Intensity (PMI), Energy Intensity (EI), Environmental Factor (E-Factor), and Reaction Mass Efficiency (RME), are evaluated, illustrating its cost-effectiveness and environmental benefits. This comprehensive approach underscores the potential of CXT as a durable and sustainable repair material for concrete infrastructure.

Development of a new heterogeneous catalyst based on triple superphosphate for the one-pot multicomponent synthesis via green strategy, accompanied by a critical assessment of environmental sustainability metrics applied to the synthesis of 2,4,5-tri and 1,2,4,5-tetra substituted imidazole heterocycle derivatives

A new catalyst, cerium phosphate (Ce(NO3)3/TSP), has been developed through a straightforward co-precipitation method. This catalyst was thoroughly characterized using techniques such as X-ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and Energy Dispersive Spectroscopy (EDS). The research focused on the application of Ce(NO3)3/TSP in the of 2,4,5-tri and 1,2,4,5-tetra substituted imidazole reaction with ammonium acetate, amine derivatives, benzil, and various aldehydes. The catalyst demonstrated outstanding performance, achieving product yields of 90-97% in just 8-10 minutes in an ethanol medium. The heterogeneity of the reaction was confirmed by a hot filtration test. This catalyst offers significant benefits, including easy recovery, reusability for at least five cycles, a simple work-up procedure, and high product yields. An evaluation of sustainability using green metrics such as the E-factor, atom economy (AE), reaction mass efficiency (RME), carbon efficiency (CE), and optimum efficiency (OE) indicated that this catalyst greatly enhances the environmental sustainability of the 2,4,5-tri and 1,2,4,5-tetra substituted imidazole reaction.

Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents.

Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.

Mimicking Ozonolysis via Mechanochemistry: Internal Alkynes to 1,2-Diketones using H5IO6.

Utilizing periodic acid as an environmentally benign oxidizing agent, this study introduces a novel mechanochemical method that mimics ozonolysis to convert internal alkynes into 1,2-diketones, showcasing effective emulation of ozone's reactivity. Notably, this oxidation occurs at room temperature in aerobic conditions, eliminating the need for toxic transition metals, hazardous oxidants, or expensive solvents. Through control experiments validating the mechanism, substantial evidence supports a concerted reaction pathway. This progress marks a significant stride toward cleaner and more efficient chemical synthesis, mitigating the environmental impact of conventional processes. Assessing the green chemistry metrics in both solvent-free and previously reported solvent-based methods, our eco-friendly protocol demonstrates an E-factor of 7.40, a 51.7 % atom economy, a 45.5 % atom efficiency, 100 % carbon efficiency, and 11.9 % reaction mass efficiency when solvents are not used.

Facile one-pot green synthesis of Aloe vera mediated silver nanoparticles and their catalytic efficiency towards organic transformations

A facile approach for the synthesis of Aloe vera mediated silver nano-particles (AgNPs) has been carried out via chemical route. The developed Aloe vera mediated AgNPs were characterized by using various techniques such as SEM, FT-IR etc. Additionally, catalytic applications of this interesting nanomaterial were utilized for the synthesis of 4-phenylthiazole- 2-amine and its derivatives. After completion of catalytic reactions, Aloe vera mediated AgNPs were easily recycled without any significant loss in catalytic activity. The robust features of the current approach involve an outstanding catalytic performance, ease of catalyst retrievability, easy work up procedure, and large substrate tolerance. Besides this, the green chemistry metrics for the products formed such as E-factor (Environment Factor), PMI (Process Mass Intensity), RME (Reaction Mass Efficiency), Atom Economy (AE) and carbon efficiency (CE) were in associated with high efficiency and selectivity which further confirms the effectiveness of this approach. This work highlights the significance of using economic and eco-friendly approach for synthesizing thiazole derivatives in good to excellent yields via Aloe vera mediated AgNPs under waste free conditions.

Visible Light Mediated Synthesis of 3‐Indolmethyl Chromones via the Cyclization of o‐Hydroxyaryl Enaminones with 3‐Indoleacetic Acids Catalyzed by Graphitic Carbon Nitride Adorned with Copper Nanoparticles

AbstractCopper nanoparticles (Cu2O NPs) supported on graphitic carbon nitride (g‐C3N4) have been introduced as an effective heterogenous catalyst for the synthesis of 3‐indolmethyl chromones (3 a–q) under visible light conditions via the cyclization of o‐hydroxyaryl enaminones with 3‐indoleacetic acids. The catalyst was thoroughly characterized using various techniques such as FT‐IR, PXRD, XPS, FE‐SEM, EDX, TEM, and HR‐TEM analysis. The optimized reaction conditions enabled the high yield production of a wide range of 3‐indolmethyl chromones in a short timespan at room temperature under visible light and method was successfully applied to the gram‐scale synthesis. Importantly, the catalyst could be reused for up to five cycles without significant decrease in its activity. This approach aligns with eco‐friendly principles, demonstrating favorable green chemistry metrics for compound 3 a, including process mass intensity (7.83), environmental impact factor (6.83), atom economy (67.56 %), reaction mass efficiency (60.76 %), chemical yield (92.37 %), mass intensity (1.64), mass productivity (60.97 %), carbon efficiency (69.15 %) and optimum efficiency (89.93 %).

Synthesis, characterization, and investigation the catalytic potential of diammonium phosphate modified with bismuth for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones through a three-component reaction: An in-depth evaluation using green metrics

A straightforward synthesis of a novel catalyst, bismuth phosphate (Bi(NO3)3/DAP), was achieved using a co-precipitation method. The resulting material underwent thorough characterization employing various techniques, including X-ray diffraction, FTIR, scanning electron microscopy (SEM), and EDX. We investigated the application of Bi(NO3)3/DAP as a catalyst in the 3,4-dihydropyrimidin-2(1H)-ones reaction between urea, ethyl acetoacetate, and various aldehydes. The results demonstrated that the catalyst exhibited excellent catalytic performance, leading to the production of products with impressive yields (89–97 %) in just 15 min in an ethanol medium. Additionally, the heterogeneity of the reaction was confirmed through a hot filtration test. Notably, this catalyst presents notable benefits, such as its easy recovery and ability to be reused for a minimum of five successive cycles, a simple work-up procedure, and the attainment of high product yields. A sustainability evaluation based on green metrics using the E-factor, atom economy (AE), reaction mass efficiency (RME), and optimum efficiency (OE) revealed that the use of a catalyst in the Biginelli reaction enhances environmental sustainability.

Efficient synthesis of novel thiadiazolo[2,3-b]quinazolin-6-ones catalyzed by diphenhydramine hydrochloride-CoCl2⋅6H2O deep eutectic solvent

In this research, a new Lewis acid-based deep eutectic solvent (LA-DES) was synthesized using diphenhydramine hydrochloride and CoCl2·6H2O, (2[HDPH]:CoCl42−), and identified by FT-IR and 1HNMR techniques. The physicochemical properties of this LA-DES, such as thermal behavior, thermal stability, and solubility in common solvents were also investigated. The catalytic ability of 2[HDPH]:CoCl42− was ascertained in the efficient synthesis of a novel array of thiadiazolo[2,3-b]quinazolin-6-one scaffolds via a one-pot three-component reaction of dimedone/1,3-cyclohexanedione, aldehydes, and 5-aryl-1,3,4-thiadiazol-2-amines/3-(5-amino-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one under solvent-free conditions. This catalyst was also successfully utilized for the synthesis of mono- and bis-thiadiazolo[2,3-b]quinazolin-6-ones from dialdehydes or bis-1,3,4-thiadiazol-2-amine. The simplicity of enforcement, short reaction time, avoidance of toxic organic solvents, scalability of the synthesis procedure, excellent atom economy, high reaction mass efficiency, and low E-factor are other outstanding advantages of this newly developed method. Furthermore, due to the convenient recovery and reuse of LA-DES, this protocol is economically justified and environmentally friendly.

Oxidation of N-trifluoromethylthio sulfoximines using NaOCl·5H2O.

N-Trifluoromethylthio sulfoximines are biologically interesting compounds, but their potential is still poorly understood. The oxidation of N-trifluoromethylthio sulfoximines led to their corresponding sulfoxide derivatives as a new class of compounds, when using sodium hypochlorite pentahydrate (NaOCl·5H2O) as a green and relatively unexplored reagent. The reactions took place with a small excess of oxidant under environmentally friendly conditions in EtOAc for 16 h at room temperature. Noteworthy distinctions of this transformation are the simplicity, high selectivity, energy and cost efficiency, minimal amounts of non-hazardous waste, isolation of most of the products without the additional need for chromatographic purification, and simple scalability to gram reactions without deterioration of the yield. The reaction exhibited excellent green chemistry metrics with high atom economy (82.0%), actual atom economy (79.5%), reaction mass efficiency (79.7%), E-factor (16.48) and a very high EcoScale score (84.5). Competitive experiments demonstrated that electron-rich substrates are more reactive than their electron-poor counterparts. Furthermore, the Suzuki-Miyaura functionalization of N-trifluoromethylsulfaneylidene sulfoximine could be achieved depending on the conditions, resulting in coupling products with or without an introduced sulfoxide moiety. Sonogashira coupling of N-trifluoromethylsulfaneylidene sulfoximine furnished the expected acetylene derivative in high yield, and the reaction conditions are compatible with the newly introduced sulfaneylidene functionality. Bromine and nickel catalysts were also shown to be deprotecting agents of the sulfoxide group. A selected N-trifluoromethylsulfaneylidene sulfoximine demonstrated its stability in water in the presence of air and in dilute hydrochloric acid, while it converted back to the parent sulfoximine under basic conditions.

Unlocking the Molecular Behavior of Natural Amine-Targeted Carbon Quantum Dots for the Synthesis of Diverse Pharmacophore Scaffolds via an Unusual Nanoaminocatalytic Route.

Despite the fact that carbon quantum dots (CQDs) have significant catalytic potential, only emblematic applications that rely on simple acid-base or hydrogen-bonding activation pathways have been reported. In this study, natural amine-targeted CQDs (NAT-CQDs) have been successfully fabricated using a sustainable technique that harnesses a renewable green source. Based on a holistic sustainable assessment, the present approach for the synthesis of NAT-CQDs surpasses previously reported methods in terms of estimated circular and good-manufacturing-practice metrics. A set of spectroscopic and analytical techniques, including FTIR, XPS, conductometric assay, pH titration, 19FNMR, and 13CNMR confirms the presence of the assessable amino-rich groups (0.0083N) at the surface of NAT-CQDs. The occurrence of surface amine groups unlocked the molecular behavior of as-prepared NAT-CQDs and makes them an unprecedented nanoaminocatalytic platform for the synthesis of diverse pharmacophore scaffolds (>40 examples) via a one-pot Knoevenagel/(aza) Michael addition reaction in water at room temperature. The assessable amine group can covalently activate carbonyl groups through nucleophilic iminium activation modes in water and facilitate the ability to build valuable and therapeutic scaffolds on a gram scale. By transferring significant molecular primacy at the frontier of nanoscale materials, NAT-CQDs can thus bridge the gap between the nanoscale and molecular domains. This protocol can also be applied for the preparation of therapeutic anticoagulant drugs, warfarin, and coumachlor. All the reactions exhibited a high atom economy, low E-factor, low process mass intensity (PMI), high reaction mass efficiency (RME), high carbon efficiency (CE), and high catalyst reusability with overall high sustainable values. NAT-CQDs show high recyclability, and the spectral data of reused catalysts indicate that the NAT-CQDs maintained their surface chemistry and electronic properties, suggesting their stability under the tested conditions. This study presents a remarkable instance of NAT-CQDs showcasing covalent catalysis. Expanding on the aforementioned design concept, the utilization of NAT-CQDs' "potential" as distinct colloidal organocatalysts in aqueous environments at the molecular level introduces valuable prospects for aminocatalytic pathways.

Unlocking the Bioactive Potential of Pomegranate Peels: A Green Extraction Approach.

Pomegranate (Punica granatum L.) is well known for its high content of bioactives, including polyphenols, flavonoids, and tannins, which have been shown to exhibit a wide range of biological activities, such as antioxidant, antimicrobial, and anticancer effects. It is worth noting that the majority of these molecules are found in the peels, which are usually disposed of after processing, causing a significant amount of waste, amounting to more than 3.6 million t/y. This work investigates microwave-assisted extraction (MAE) in water for the recovery of antioxidants from pomegranate peels (PP), including the optimisation of temperature and extraction times. The total phenolic, anthocyanin, flavonoid, and tannin contents of the recovered extracts were determined, as well as their antioxidant activities, which were found to be 356.35 mgGAE/gExtr, 303.97 µgCy3G/gExtr, 37.28 mgQE/gExtr, 56.48 mgGAE/gExtr, and 5.72 mmolTE/gExtr, respectively (according to the adopted reference). All results were compared with those obtained using a conventional protocol. In addition, the potential for water recycling by means of downstream nanofiltration in optimised MAE was investigated, leading to overall water reuse of approx. 75%. Power consumption (20.92 W/mgGAE) and common green metrics, Reaction Mass Efficiency (RME), E-Factor, and the Process Mass Intensiti/efficiency (PMI, PME), were considered in evaluating the proposed PP valorisation strategy. Finally, the biological activities of the main products were assessed. The antimicrobial properties of the PP extracts against three Gram-positive and three Gram-negative bacteria and their antiproliferative activity towards human cancer cells were tested. S. aureus bacteria was the most susceptible to the PP extracts. All tested products displayed antiproliferative activity against HeLa cells when higher concentrations were tested, with D-PP/NF (obtained from dried PP and sequential nanofiltration) being the most effective. This result was also confirmed via clonogenic analysis, which generally indicated the possible anti-cancer activity of pomegranate peel extracts obtained using this green approach.

The assessment of sustainability indicators for triglycerides transesterification with alcohols catalyzed by ion exchange resins

The research was aimed at determining the dependences of sustainability indicators on the parameters of the sunflower oil transesterification with ethyl, propyl, and butyl alcohol catalyzed by anion exchange resin AV-17-8 with OH– ions or cation exchange resin KU-2-8 with H+ or immobilized Zn2+, Sn2+, Ni2+, Co2+, and Cu2+ ions. Such sustainability indicators as the E-factor, atomic efficiency, mass intensity and mass productivity, reaction mass efficiency, stoichiometric factor, etc., have been determined. We established that sustainability indicators of transesterification catalyzed by ion exchange resins depend on the yield of higher fatty acid esters that can be achieved by immobilized metal ions. The unreacted alcohol regeneration significantly reduces the E-factor value and increases the reaction mass efficiency. During the sunflower oil ethanolysis, the minimum E-factor value is achieved at the ethyl alcohol:triglyceride molar ratio corresponding to the maximum yield of higher fatty acid esters. The reaction mass efficiency calculated without considering the unreacted alcohol regeneration is one of the criteria for determining its regeneration expediency. The sustainability indicators are the additional criteria for selecting optimal conditions of the sunflower oil transesterification with aliphatic alcohols catalyzed by ion exchange resins. The calculated sustainability indicators indicate that the investigated ion exchange resins as heterogeneous transesterification catalysts provide a high yield of higher fatty acid esters. Using the researched catalysts ensures a low E-factor, making the process environmentally friendly.

Nitrogen-Enriched Biguanidine-Functionalized Cobalt Ferrite Nanoparticles as a Heterogeneous Base Catalyst for Knoevenagel Condensation under Solvent-Free Conditions.

Designing efficient, economical heterogeneous catalysts for the Knoevenagel condensation reaction is highly significant owing to the importance of reaction products in industries as well as pharmaceutics. Herein, we have designed and synthesized biguanidine-functionalized basic magnetically retrievable cobalt ferrite nanoparticles (CFNPs) for the synthesis of Knoevenagel condensation products using benzaldehydes and active methylene compounds (malononitrile/ethyl cyanoacetate/cyanoacetamide). Several advanced techniques, such as Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and vibration sample magnetometry (VSM), were utilized to precisely characterize the catalyst. The robust features of the current approach involve outstanding catalytic performance, solvent-free reaction conditions, ease of catalyst retrievability, easy workup procedure, large substrate tolerance, high turnover frequency (TOF) values (up to 486.88 h-1), values of green chemistry metrics such as E-factor (0.15), reaction mass efficiency (RME) value (87.07%), carbon efficiency (93.4%), and atom economy (AE) value (88.10%) close to their ideal values, and recyclability up to eight runs without a considerable reduction in activity, boosting the appeal of this approach from a commercial and ecological point of view.

Learning Green Chemistry Principles by Comparing Three Synthetic Routes to a Copper-NHC (NHC = N-heterocyclic carbene) Complex

The implementation of a laboratory exercise in an undergraduate chemistry course, where students perform a comparison of three different synthetic methods toward [Cu(Cl)(IPr)]-complexes (IPr = N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), is described. The students are introduced to the continuous improvement of reactions in terms of green chemistry and are provided a taste of mechanochemistry as a synthetic methodology. The direct comparison of three methods leading to the copper complexes provides an opportunity to teach green chemistry metrics including atom economy, environmental factor, mass intensity, reaction mass efficiency, and optimum efficiency, as well as Green Star; and challenges them to question the use of solvents in chemical syntheses.

Microcrystalline Cellulose Decorated with Fe3O4 Nanoparticle Catalysts for the Microwave-Assisted Synthesis of Thioglyoxamides

Ferrite nanoparticles (Fe3O4 NPs) supported on microcrystalline cellulose (MCC) are introduced as an active nanocatalyst for the preparation of the α-keto thioglyoxamides via a microwave (MW)-assisted protocol. This prepared catalyst shows consistent particle size of Fe3O4 NPs as characterized by PXRD, XPS, SEM, EDS, EDX, TEM, HR-TEM, and FT-IR analysis. A wide variety of thioglyoxamindes are synthesized under optimized reaction conditions to afford a good yield in a short time. Importantly, the presented catalyst can be recycled up to five cycles with no major loss in its activity and is equally relevant for the gram-scale synthesis of thioglyoxamides. This environmentally benign approach offers several advantages and displays good green chemistry metrics (GCM), namely, process mass intensity (PMI), E-factor and atom economy (AE), and reaction mass efficiency (RME).

Waste-minimized continuous flow copper-catalyzed azide-alkyne cycloaddition with low metal contamination

Metal contamination is a waste-generating and serious issue in the synthesis of chemicals, in particular in the case of products with biological activity. The appropriate selection of operating conditions plays a crucial role in the abatement of metal leaching in solution and associated wastes. Herein we report a waste-minimized continuous flow process for the synthesis of 1,4-disubstituted β-keto 1,2,3-triazoles exploiting the use of a copper tube flow reactor (CTFR). The selection of the proper azeotropic mixture allowed an almost quantitative recovery of the reaction medium greatly influencing the E-factor of the protocol. A thorough understanding of the main parameters affecting the waste generation was given by calculation of the E-factor distribution for different work-up tested under batch and flow conditions. Furthermore, the measurement of different green metrics (AE: Atom Economy, SF: Stoichiometric Factor, RME: Reaction Mass Efficiency, and MRP: Mass Recover Parameter) clearly demonstrated the benefits of the flow scale-up that allowed to perform a low environmental footprint CuAAC reaction.