Phthalocyanines Synthesis: A State-of-The-Art Review of Sustainable Approaches Through Green Chemistry Metrics.

Driven by escalating environmental concerns, synthetic chemistry faces an urgent need for a green revolution. Green chemistry, with its focus on low environmental impacting chemicals and minimized waste production, emerges as a powerful tool in addressing this challenge. Metrics such as the E-factor guide the design of environmentally friendly strategies for chemical processes by quantifying the waste generated in obtaining target products, thus enabling interventions to minimize it. Phthalocyanines (Pcs), versatile molecules with exceptional physical and chemical properties, hold immense potential for technological applications. This review aims to bridge the gap between green chemistry and phthalocyanine synthesis by collecting the main examples of environmentally sustainable syntheses documented in the literature. The calculation of the E-factor of a selection of them provides insights on how crucial it is to evaluate a synthetic process in its entirety. This approach allows for a better evaluation of the actual sustainability of the phthalocyanine synthetic process and indicates possible strategies to improve it.

Pyrrole Compounds from the Two-Step One-Pot Conversion of 2,5-Dimethylfuran for Elastomer Composites with Low Dissipation of Energy.

A one-pot, two-step process was developed for the preparation of pyrrole compounds from 2,5-dimethylfuran. The first step was the acid-catalyzed ring-opening reaction of 2,5-dimethylfuran (DF), leading to the formation of 2,5-hexanedione (HD). A stoichiometric amount of water and a sub-stoichiometric amount of sulfuric acid were used by heating at 50 °C for 24 h. Chemically pure HD was isolated, with a quantitative yield (up to 95%), as revealed by 1H-NMR, 13C-NMR, and GC-MS analyses. In the second step, HD was used as the starting material for the synthesis of pyrrole compounds via the Paal-Knorr reaction. Various primary amines were used in stoichiometric amounts. 1H-NMR, 13C-NMR, ESI-Mass, and GC-Mass analyses confirmed that pyrrole compounds were prepared with very good/excellent yields (80-95%), with water as the only co-product. A further purification step was not necessary. The process was characterized by a very high carbon efficiency, up to 80%, and an E-factor down to 0.128, whereas the typical E-factor for fine chemicals is between 5 and 50. Water, a co-product of the second step, can trigger the first step and therefore make the whole process circular. Thus, this synthetic pathway appears to be in line with the requirements of a sustainable chemical process. A pyrrole compound bearing an SH group (SHP) was used for the functionalization of a furnace carbon black (CB). The functionalized CB (CB/SHP) was utilized in place of silica, resulting in a 15% mass reduction of reinforcing filler, in an elastomeric composite based on poly(styrene-co-butadiene) from solution anionic polymerization and poly(1,4-cis-isoprene) from Hevea Brasiliensis. Compared to the silica-based composite, a reduction in the Payne effect of about 25% and an increase in the dynamic rigidity (E' at 70 °C) of about 25% were obtained with CB/SHP.

Industrially Relevant Enzyme Cascades for Drug Synthesis and Their Ecological Assessment.

Environmentally friendly and sustainable processes for the production of active pharmaceutical ingredients (APIs) gain increasing attention. Biocatalytic synthesis routes with enzyme cascades support many stated green production principles, for example, the reduced need for solvents or the biodegradability of enzymes. Multi-enzyme reactions have even more advantages such as the shift of the equilibrium towards the product side, no intermediate isolation, and the synthesis of complex molecules in one reaction pot. Despite the intriguing benefits, only a few enzyme cascades have been applied in the pharmaceutical industry so far. However, several new enzyme cascades are currently being developed in research that could be of great importance to the pharmaceutical industry. Here, we present multi-enzymatic reactions for API synthesis that are close to an industrial application. Their performances are comparable or exceed their chemical counterparts. A few enzyme cascades that are still in development are also introduced in this review. Economic and ecological considerations are made for some example cascades to assess their environmental friendliness and applicability.

Cascade Processes with Micellar Reaction Media: Recent Advances and Future Directions.

Reducing the use of solvents is an important aim of green chemistry. Using micelles self-assembled from amphiphilic molecules dispersed in water (considered a green solvent) has facilitated reactions of organic compounds. When performing reactions in micelles, the hydrophobic effect can considerably accelerate apparent reaction rates, as well as enhance selectivity. Here, we review micellar reaction media and their potential role in sustainable chemical production. The focus of this review is applications of engineered amphiphilic systems for reactions (surface-active ionic liquids, designer surfactants, and block copolymers) as reaction media. Micelles are a versatile platform for performing a large array of organic chemistries using water as the bulk solvent. Building on this foundation, synthetic sequences combining several reaction steps in one pot have been developed. Telescoping multiple reactions can reduce solvent waste by limiting the volume of solvents, as well as eliminating purification processes. Thus, in particular, we review recent advances in "one-pot" multistep reactions achieved using micellar reaction media with potential applications in medicinal chemistry and agrochemistry. Photocatalyzed reactions in micellar reaction media are also discussed. In addition to the use of micelles, we emphasize the process (steps to isolate the product and reuse the catalyst).

Modern Methods for the Sustainable Synthesis of Metalloporphyrins.

Metalloporphyrins are involved in many and diverse applications that require the preparation of these compounds in an efficient manner, which nowadays, also involves taking into consideration sustainability issues. In this context, we use ball milling mechanochemistry and sonochemistry for the rational development of synthetic strategies for the sustainable preparation of metalloporphyrins. Zinc, copper, cobalt and palladium complexes of hydrophobic porphyrins were obtained in high yields and under mechanical action with a moderate excess of the metal salt, without any solvent or additive. Sonochemistry prove to be a good alternative for the preparation of metal complexes of water-soluble porphyrins in good yields and short reaction times. Both strategies have good sustainability scores, close to the ideal values, which is useful in comparing and helping to choose the more adequate method.

Environmental Assessment of Enzyme Production and Purification.

The importance of bioprocesses has increased in recent decades, as they are considered to be more sustainable than chemical processes in many cases. E factors can be used to assess the sustainability of processes. However, it is noticeable that the contribution of enzyme synthesis and purification is mostly neglected. We, therefore, determined the E factors for the production and purification of 10 g enzymes. The calculated complete E factor including required waste and water is 37,835 gwaste·genzyme-1. This result demonstrates that the contribution of enzyme production and purification should not be neglected for sustainability assessment of bioprocesses.

Hydroxyl alkyl ammonium ionic liquid assisted green and one-pot regioselective access to functionalized pyrazolodihydropyridine core and their pharmacological evaluation.

Herein our team explored a promising synthetic trail to Functionalized pyrazolodihydropyridine core using hydroxyl alkyl ammonium ionic liquid via one-pot fusion of 3-methyl-1-phenyl-1H-pyrazole-5-amine, different heterocyclic aldehydes and 1, 3-Cyclic diones. The aimed compounds were obtained by Domino-Knoevenagel condensation and Michael addition followed by cyclization. The reaction transformation involves the formation of two CC and one CN bond formation. The perspective of the present work is selectively approached to Functionalized pyrazolodihydropyridine core excluding other potential parallel reactions under environmentally benign reaction condition. The present protocol show features such as the low E-factor, ambiphilic behavior of ionic liquid during reaction transformation, scale-up to a multigram scale, reusability of the ionic liquid, mild reaction condition, and produce water as a byproduct. All newly derived compounds were evaluated for their in vitro biological activities. In preliminary biological studies compound, 4c showed better potency than the standard drug ampicillin against Gram-negative bacteria (E. coli); the compound 4i exhibited outstanding activity against S. aeruginosa which is far better than ampicillin, chloramphenicol, and ciprofloxacin. The compound 4m was found more potent against C. albicans, than that of griseofulvin and show equipotency to nystatin whereas, in preliminary antitubercular screening, compound 4o was exhibited more potency than rifampicin. Noteworthy compounds 4f and 4i were found most active in antiproliferative screening.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.

HandaPhos: A General Ligand Enabling Sustainable ppm Levels of Palladium-Catalyzed Cross-Couplings in Water at Room Temperature.

The new monophosphine ligand HandaPhos has been identified such that when complexed in a 1:1 ratio with Pd(OAc)2, enables Pd-catalyzed cross-couplings to be run using ≤1000 ppm of this pre-catalyst. Applications to Suzuki-Miyaura reactions involving highly funtionalized reaction partners are demonstrated, all run using environmentally benign nanoreactors in water at ambient temperatures. Comparisons with existing state-of-the-art ligands and catalysts are discussed herein.

Green Chemistry Metrics with Special Reference to Green Analytical Chemistry.

The concept of green chemistry is widely recognized in chemical laboratories. To properly measure an environmental impact of chemical processes, dedicated assessment tools are required. This paper summarizes the current state of knowledge in the field of development of green chemistry and green analytical chemistry metrics. The diverse methods used for evaluation of the greenness of organic synthesis, such as eco-footprint, E-Factor, EATOS, and Eco-Scale are described. Both the well-established and recently developed green analytical chemistry metrics, including NEMI labeling and analytical Eco-scale, are presented. Additionally, this paper focuses on the possibility of the use of multivariate statistics in evaluation of environmental impact of analytical procedures. All the above metrics are compared and discussed in terms of their advantages and disadvantages. The current needs and future perspectives in green chemistry metrics are also discussed.

Aerobic oxidation in nanomicelles of aryl alkynes, in water at room temperature.

On the basis of the far higher solubility of oxygen gas inside the hydrocarbon core of nanomicelles, metal and peroxide free aerobic oxidation of aryl alkynes to ß-ketosulfones has been achieved in water at room temperature. Many examples are offered that illustrate broad functional group tolerance. The overall process is environmentally friendly, documented by the associated low E Factors.

Surface modification of cellulose with succinic anhydride in dimethyl sulfoxide using potassium carbonate as a catalyst.

Cellulose succinates (CSs) having degrees of substitution (DSs) ranging from 0.78 to 2.77 were successfully obtained by reacting cellulose with succinic anhydride (SA) in dimethyl sulfoxide at room temperature using a small amount of inexpensive solid potassium carbonate as a catalyst. Interestingly, CSs with higher DS values were obtained with a much smaller amount of catalyst than previously reported. Moreover, it is possible to control the DS by tailoring the reaction time and mass ratio of cellulose/SA. The hydroxyl groups at the C-6, C-2, and C-3 positions were the main esterification positions. In this process, most of the raw materials are either incorporated into the product or are recoverable. The E-factor, which reflects the sustainability of a given process, was demonstrated to be reduced by 93% by recovering the raw materials.

Eco-Friendly Catalytic Synthesis of Top Value Chemicals from Valorization of Cellulose Waste.

The total amount of cellulose from paper, wood, food, and other human activity waste produced in the EU is in the order of 900 million tons per year. This resource represents a sizable opportunity to produce renewable chemicals and energy. This paper reports, unprecedently in the literature, the usage of four different urban wastes such as cigarette butts, sanitary pant diapers, newspapers, and soybean peels as cellulose fonts to produce valuable industrial intermediates such as levulinic acid (LA), 5-acetoxymethyl-2-furaldehyde (AMF), 5-(hydroxymethyl)furfural (HMF), and furfural. The process is accomplished by the hydrothermal treatment of cellulosic waste using both Brønsted and Lewis acid catalysts such as CH3COOH (2.5-5.7 M), H3PO4 (15%), and Sc(OTf)3 (20% w:w), thus obtaining HMF (22%), AMF (38%), LA (25-46%), and furfural (22%) with good selectivity and under relatively mild conditions (T = 200 °C, time = 2 h). These final products can be employed in several chemical sectors, for example, as solvents, fuels, and for new materials as a monomer precursor. The characterization of matrices was accomplished by FTIR and LCSM analyses, demonstrating the influence of morphology on reactivity. The low e-factor values and the easy scale up render this protocol suitable for industrial applications.

UV-dependent freshwater effect factor of nanoscale titanium dioxide for future life cycle assessment application.

Environmental impacts of nanoscale titanium dioxide (TiO2 ) should be assessed throughout the lifetime of nanoparticles (NPs) to improve the state of knowledge of the overall sustainability. Life cycle assessment (LCA) has been previously recognized as a promising approach to systematically evaluating environmental impacts of NPs. As a result of their unique nanospecific properties, characterization factors (CF) were previously used for compensating the release and potential impacts of TiO2 NPs. However, because TiO2 NPs are known to generate reactive oxygen species and elicit toxicity to freshwater organisms, the lack of adequate UV-dependent effect factors (EFs) remains a major shortcoming when addressing their life cycle impacts. To complement the LCA of TiO2 -NPs-enabled products under their specific applications, we recapitulated the freshwater toxicity of TiO2 NPs and then modeled in USEtox to determine trophic level EF ranges under UV and non-UV exposure conditions. Results indicate that EFs derived for non-UV exposure were 52 (42.9-65) potentially affected fraction (PAF) m3 /kg, and combined toxicity data derived EFs were 70.1 (55.6-90.5) PAF m3 /kg. When considering only the UV-induced exposure condition, the modeled EF increased to 500 (333-712) PAF m3 /kg. Our work highlights that case-dependent EFs should be considered and applied to reflect more realistic ecological impacts and illustrate comprehensive life cycle environmental impacts for nanoenabled products. Integr Environ Assess Manag 2023;19:578-585. © 2022 SETAC.

Environmentally benign solid catalysts for sustainable biodiesel production: A critical review.

Versatile bio-derived catalysts have been under dynamic investigation as potential substitutes to conventional chemical catalysts for sustainable biodiesel production. This is because of their unique, low-cost benefits and production processes that are environmentally and economically acceptable. This critical review aspires to present a viable approach to the synthesis of environmentally benign and cost-effective heterogeneous solid-base catalysts from a wide range of biological and industrial waste materials for sustainable biodiesel production. Most of these waste materials include an abundance of metallic minerals like potassium and calcium. The different approaches proposed by researchers to derive highly active catalysts from large-scale waste materials of a re-usable nature are described briefly. Finally, this report extends to present an overview of techno-economic feasibility of biodiesel production, its environmental impacts, commercial aspects of community-based biodiesel production and potential for large-scale expansion.

Low waste process of rapid cellulose transesterification using ionic liquid/DMSO mixed solvent: Towards more sustainable reaction systems.

The recent progress in the manufacturing of new functional cellulose-derived materials shows that the renewable side of these materials does not ensure sustainable development. In contrast, reaction/process design and waste minimization play a key role here. Herein, reactive extrusion was used as a fast method for cellulose transesterification with vinyl laurate in 1-ethyl-3-methylimidazolium acetate (EmimOAc)/DMSO system. It was demonstrated that cellulose laurate can be synthesized with high reaction efficiency (91 %). The low amount of solvent during the process provides high cellulose concentration (20 wt%) mild chemical modification within minutes and without any depolymerization. Temperature has a significant influence on the reaction kinetics. To examine the sustainability of the process E-factor was employed. Processing properties of obtained cellulose laurates were investigated. Samples with DS of 2.5 and higher can be easily extruded showing low melt viscosity. EmimOAc was recovered and reused for subsequent cellulose transesterification exhibiting high catalytic activity.

A critical analysis of environmental sustainability metrics applied to green synthesis of nanomaterials and the assessment of environmental risks associated with the nanotechnology.

Nanotechnology is one of the most relevant scientific areas today due to its multiple applications in fields such as medicine, environmental remediation, information technology and energy conversion. This importance has led to the need to advance in the development of environmentally sustainable and safe nanomaterials by incorporating the principles of green chemistry during their synthesis and in their applications. However, this qualitative framework of thought does not offer minimum criteria for the use of the term "green", and therefore, this adjective is commonly used to refer to bio-based or nanotechnological processes without taking into account their net ecological impact. In this context, environmental sustainability metrics can be applied to nanotechnology to compare, optimize and quantify the environmental sustainability of synthesis procedures. This review provides an overview of green chemistry and its application in nanotechnology, but also an analysis of the use of green chemistry principles in the development of bio-based nanobiotechnology and nanosynthesis, with special emphasis on the use of sustainability's metrics for the quantitative analysis of nanomaterial synthesis protocols. These include: Atom Economy, E-factor, Process Mass Intensity, Energy Intensity, and Life Cycle Analysis.

Green Chemistry Meets Asymmetric Organocatalysis: A Critical Overview on Catalysts Synthesis.

Can green chemistry be the right reading key to let organocatalyst design take a step forward towards sustainable catalysis? What if the intriguing chemistry promoted by more engineered organocatalysts was carried on by using renewable and naturally occurring molecular scaffolds, or at least synthetic catalysts more respectful towards the principles of green chemistry? Within the frame of these questions, this Review will tackle the most commonly occurring organic chiral catalysts from the perspective of their synthesis rather than their employment in chemical methodologies or processes. A classification of the catalyst scaffolds based on their E factor will be provided, and the global E factor (EG factor) will be proposed as a new green chemistry metric to consider, also, the synthetic route to the catalyst within a given organocatalytic process.

Shielding Effect of Micelle for Highly Effective and Selective Monofluorination of Indoles in Water.

Highly selective direct monofluorination of indoles and arenes was developed through an approach that allows site-specific solubility of substrate and fluorine source in the micelle. This approach was highly selective for a broad range of substrates with excellent functional group tolerance. Differences in binding constant and solubility of indoles and arenes in the micelle allowed the fine-tuning of selectivity. Control experiments suggested a radical pathway and provided insight into the role of micelles of the environmentally benign amphiphile PS-750-M. Dynamic light scattering experiments strongly indicated the site-specific solubility of the substrate and fluorine source. The methodology was successfully adapted to gram scale, and the E-factor established from a recycle study indicated that the process is environmentally responsible and sustainable.

Increased Biobutanol Production by Mediator-Less Electro-Fermentation.

A future bio-economy should not only be based on renewable raw materials but also in the raise of carbon yields of existing production routes. Microbial electrochemical technologies are gaining increased attention for this purpose. In this study, the electro-fermentative production of biobutanol with C. acetobutylicum without the use of exogenous mediators is investigated regarding the medium composition and the reactor design. It is shown that the use of an optimized synthetic culture medium allows higher product concentrations, increased biofilm formation, and higher conductivities compared to a synthetic medium supplemented with yeast extract. Moreover, the optimization of the reactor system results in a doubling of the maximum product concentrations for fermentation products. When a working electrode is polarized at -600 mV vs. Ag/AgCl, a shift from butyrate to acetone and butanol production is induced. This leads to an increased final solvent yield of YABE = 0.202 g g-1 (control 0.103 g g-1 ), which is also reflected in a higher carbon efficiency of 37.6% compared to 23.3% (control) as well as a fourfold decrease in simplified E-factor to 0.43. The results are promising for further development of biobutanol production in bioelectrochemical systems in order to fulfil the principles of Green Chemistry.