Turning mustard gas chemistry into green chemistry: a new tool for pharmaceutical synthesis

N,N -dialkyl ethylamine moiety can be found in numerous scaffolds of macromolecules, catalysts and especiallypharmaceuticals such as Tamoxifen, Raloxifene, Amiodarone, Phenyltoloxamine, Trifenagrel and Trimethobenzamide.Common synthetic procedures for its incorporation in a substrate rely on the use of a nitrogen mustard gas or onmultistep syntheses featuring chlorine hazardous/toxic chemistry. Herein are reported our latest results on the one-potsynthetic approach for the introduction of the N,N -dialkyl ethylamine moiety in different phenolic substrates via dialkylcarbonate chemistry. In a typical reaction, 2-dimethylaminoethanol was reacted with a nucleophile (a phenolic scaffold)and dialkyl carbonate (DAC), i.e., diethyl carbonate (DEC), in the presence of a base. In particular, DEC was used for thein-situ formation of ß-aminocarbonate (mustard carbonate) that in turn acts as an alkylating agent via nitrogen nitrogenanchimeric assistance. Different substrates were investigated including precursors of commercially available drugsgiving the related alkylated compound in good to quantitative yields. This one-pot alkylation approach is a striking example of chlorine-free direct substitution of an alcohol, indicated as oneof the key Green Chemistry research areas for pharmaceuticals manufacturers. Furthermore, an in vitro toxicity studyhas been conducted on ß-aminocarbonate and its alcohol precursor, giving an insight into the cytotoxicity values of thereagents for the synthetic procedure proposed

What do we know about the ecotoxicological implications of the rare earth element Gadolinium in aquatic ecosystems?

Gadolinium (Gd) is one of the most commercially exploited rare earth elements, commonly employed in magnetic resonance imaging as a contrast agent. The present review was performed aiming to identify the Gd concentrations in marine and freshwater environments. In addition, information on Gd speciation in the environment is discussed, in order to understand how each chemical form affects its fate in the environment. Biological responses caused by Gd exposure and its bioaccumulation in different aquatic invertebrates are also discussed. This review was devoted to aquatic invertebrates, since this group of organisms includes species widely used as bioindicators of pollution and they represent important resources for human socio-economic development, as edible seafood, fishing baits and providing food resources for other species. From the literature, most of the published data are focused on freshwater environments, revealing concentrations from 0.347 to 80 μg/L, with the highest Gd anomalies found close to highly industrialized areas. In marine environments, the published studies identified a range of concentrations between 0.36 and 26.9 ng/L (2.3 and 171.4 pmol/kg), reaching 409.4 ng/L (2605 pmol/kg) at a submarine outfall. Concerning the bioaccumulation and effects of Gd in aquatic species, most of the literature regards to freshwater species, revealing concentration ranging from 0.006 to 0.223 μg/g, with high variability in the bioaccumulation extent according to Gd complexes chemical speciation. Conversely, no field data concerning Gd bioaccumulation in tissues of marine species have been published. Finally, impacts of Gd in invertebrate aquatic species were identified at different biological levels, including alterations on gene expression, cellular homeostasis, shell formation, metabolic capacity and antioxidant mechanisms. The information here presented highlights that Gd may represent an environmental threat and a risk to human health, demonstrating the need for further research on Gd toxicity towards aquatic wildlife and the necessity for new water remediation strategies

Alkyl Levulinates from Furfuryl Alcohol Using CT151 Purolite as Heterogenous Catalyst: Optimization, Purification, and Recycling

Commercially available Purolite CT151 demonstrated to be an efficient acid catalyst for the synthesis of alkyl levulinates via alcoholysis of furfuryl alcohol (FA) at mild temperatures (80–120 °C) and short reaction time (5 h). Reaction conditions were first optimized for the synthesis of ethyl levulinate and then tested for the preparation of methyl-, propyl-, isopropyl-, butyl, sec-butyl- and allyl levulinate. Preliminary scale-up tests were carried out for most of the alkyl levulinates (starting from 5.0 g of FA) and the resulting products were isolated as pure by distillation in good yields (up to 63%). Furthermore, recycling experiments, conducted for the preparation of ethyl levulinate, showed that both the Purolite CT151 and the exceeding ethanol can be recovered and reused for four consecutive runs without any noticeable loss in the catalyst activit

SUSTAINABLE GRAM-SCALE SYNTHESES OF FURANICS

Among the numerous bio-based platform chemicals - key molecules of the Biorefinery research field - a series of furan-based compounds easily synthetised from D-fructose has captured the scientists’ attention in consideration of their potential market applications. An archetype of these molecules is 5-hydroxymethylfurfural (HMF), a building block that has found numerous applications in the synthesis of chemicals, materials, bio-based polymers and fuels

Multi gram scale synthesis of HMF and comparative environmental evaluation

5-Hydroxymethylfurfural (HMF) is a bio-based platform chemical that can be used as building block to produce complex and useful compounds with diverse applicability, in particular, bio-based polymers, materials and fuels [1], [2]. Even though HMF synthesis holds promise for a greener future, with the current state of technology the high production cost limits its competitiveness at an industrial scale[1]. In this project our main goal is to develop an optimized procedure for the synthesis of HMF that will allow us to perform scale-up reactions with competitive yields with a green mindset. The synthesis of HMF from the dehydration of D-fructose, already investigated by our research group[2], was performed with a heterogeneous acid catalyst using various conditions in different settings: autoclave, sonificator and microwave oven. The best results were obtained employing a stainless-steel autoclave which allowed a large scale HMF production using up to forty grams of D-fructose as starting material. The final product was recovered from the crude mixture and purified by a custom-made crystallization procedure. Finally, green metrics were used to evaluate the greenness of the reaction in comparison with previously reported works[3]

Sintesi del metil estere dell’acido furan dicarbossilico (FDME) a partire dall’acido galattarico tramite la chimica del dimetil carbonato

L’acido 2,5-furandicarbossilico (FDCA) è stato studiato estensivamente come monomero per per la produzione di poliesteri1 come il polietilene furanoato (PEF), considerato il più valido biosostituto del polietilene tereftalato (PET). Il PEF possiede notevoli proprietà meccaniche e termiche, una forte barriera ai gas, un basso carbon footprint e una ridotta produzione di gas serra durante la sua sintesi.2 La maggior parte dei processi sintetici per l’ FDCA utilizzano zuccheri edibili (glucosio e fruttosio) come substrati attraverso la produzione del 5-idrossimetilfurfurale (HMF) come intermedio.3 Il principale svantaggio di questo processo riguarda l’instabilità, il costo elevato e la difficile separazione e purificazione dell’HMF, che portano alla formazione di umine, abbassando notevolmente la resa della reazione.4 Pochi studi si sono invece concentrati sulla produzione di FDCA a partire da substrati differenti. Ad esempio questo composto può anche essere sintetizzato a partire dai cosiddetti acidi aldarici, i derivati dicarbossilici monosaccaridi (C6), che possono essere ottenuti sia tramite ossidazione degli stessi o direttamante dalla buccia di alcuni agrumi come cedro e arancia.5 Partendo da queste premesse, il seguente studio riporta una sintesi alternativa per la produzione del dimetil estere dell’acido 2,5-furandicarbossilico (FDME) a partire dall’acido galattarico (o mucico) tramite la chimica del dimetil carbonato (DMC). In una tipica reazione l’acido galattarico viene fatto reagire con DMC in presenza di Amberlyst-36 come catalizzatore acido. La reazione viene condotta in autocalve a 200 °C per 2 ore. Il prodotto può essere facilmente ottenuto come solido cristallino tramite purificazione con carbone attivo con resa del 70 %. Inoltre, sulla base dei diversi intermedi di reazione identificati, è stato ipotizzato un possibile meccanismo di reazione che evidenzia l’indispensabile contributo del dimetilcarbonato nella formazione del prodotto

A scale-up procedure to Dialkyl Carbonates: purification, chemical physical properties, biodegradability and cytotoxicity tests

Among the different dimethyl carbonate (DMC) derivatives, dialkyl carbonates DACs are extensively investigated as safe alternatives to chlorine reagents. In fact, they can replace alkyl halides and dimethyl sulfate in alkylation and carbonylation reactions as well as phosgene and its derivatives in the alkoxycarbonylation ones. In this work we explored the high yielding scale-up synthesis of non-commercially available or expensive dialkyl carbonates (DACs) via transcarbonylation reactions of an alcohol with dimethyl carbonate (DMC) promoted by a nitrogen-based organocatalyst. Compared to previously published works, the proposed procedure has been customized for DACs large scale production (up to 70 mL of product obtained). Purification of these compounds has been achieved by fractional distillation and the exceeding reagents have been recovered and recycled. The selected DACs for this study include both symmetrical and unsymmetrical compounds, incorporating several alkyl, alkoxyalkyl, alkylamino and alkylthio functional groups. The chemical-physical properties of the new DACs have been also evaluated, as well as their water solubility. Furthermore, both biodegradability and cytotoxicity tests have been carried out to investigate the effects of the different substituents on the greenness of these potential solvents and reagents

Dialkyl carbonates: scale-up synthesis and application as green solvents for PVDF membranes preparation

Dialkyl carbonates (DACs) are well-known green solvents and reagents that have been extensively investigated as safe alternatives to chlorine-based compounds. In fact, they can replace alkyl halides and dimethyl sulfate in alkylation and carbonylation reactions as well as phosgene and its derivatives in alkoxycarbonylation ones. Recently we have developed a high yielding scale-up synthesis of non-commercially available or expensive DACs via transcarbonylation reactions of an alcohol with dimethyl carbonate (DMC) promoted by the nitrogen-based organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene TBD. Compared to previously published works, the proposed procedure has been customized for DACs large scale production (up to 100 mL of product obtained). Purification of these compounds has been achieved by fractional distillation and the exceeding reagents have been recovered and recycled. Selected DACs for this study include both symmetrical and unsymmetrical compounds, incorporating several alkyl, alkoxyalkyl, alkylamino and alkylthio functional groups. Chemical-physical properties of the new DACs have been also evaluated, as well as their water solubility. Furthermore, biodegradability and cytotoxicity tests have been carried out to investigate the effects of the different substituents on the greenness of these potential solvents and reagents. DACs application as green solvents for membrane preparation was next investigated, using non-solvent induced phase separation (NIPS) and vapor induced phase separation (VIPS) techniques, achieving both porous and plain membranes [4]. Morphology, additives effect, physical-chemical and mechanical proprieties as well as their performances in terms of water permeability and rejection were evaluated and compared to membranes obtained using commercially available cyclic carbonates (namely ethylene carbonate – EC and propylene carbonate – PC)

How Ulva lactuca can influence the impacts induced by the rare earth element Gadolinium in Mytilus galloprovincialis? The role of macroalgae in water safety towards marine wildlife

Rare earth elements (REEs) are gaining growing attention in environmental and ecotoxicological studies due to their economic relevance, wide range of applications and increasing environmental concentrations. Among REEs, special consideration should be given to Gadolinium (Gd), whose wide exploitation as a magnetic resonance imaging (MRI) contrast agent is enhancing the risk of its occurrence in aquatic environments and impacts on aquatic organisms. A promising approach for water decontamination from REEs is sorption, namely through the use of macroalgae and in particular Ulva lactuca that already proved to be an efficient biosorbent for several chemical elements. Therefore, the present study aimed to evaluate the toxicity of Gd, comparing the biochemical effects induced by this element in the presence or absence of algae. Using the bivalve species Mytilus galloprovincialis, Gd toxicity was evaluated by assessing changes on mussels’ metabolic capacity and oxidative status. Results clearly showed the toxicity of Gd but further revealed the capacity of U. lactuca to prevent injuries to M. galloprovincialis, mainly reducing the levels of Gd in water and thus the bioaccumulation and toxicity of this element by the mussels. The results will advance the state of the art not only regarding the effects of REEs but also with regard to the role of algae in accumulation of metals and protection of aquatic organisms, generating new insights on water safety towards aquatic wildlife and highlighting the possibility for resources recovery

Synthesis of 2,5-furandicarboxylic acid esters from galactaric acid

2,5-Furandicarboxylic acid (FDCA) has been extensively studied as monomer for the production of polyesters[1] such as polyethylene furanoate (PEF), considered as one of the most valuable bio-based substitute of the petroleum-derived polyethylene terephthalate (PET). [2] Most of the synthetic processes to FDCA employ glucose and fructose as substrates, with the formation of 5-hydroxymethyl furfural (HMF) as an intermediate.[1] The main disadvantage of this process regards the intrinsic instability of HMF, together with its high market price and its difficult separation and purification, which ultimately lead to the production of humins, drastically lowering the overall reaction yield.[3] Few studies focused instead on the production of FDCA from different substrates. In fact, FDCA can be synthetized starting from aldaric acids, which can be obtained either via oxidation of sugars or directly extracted from citruses peel.[4] From these premises, the present study reports an alternative synthetic procedure for the production of 2,5-furandicarboxylic acid dimethyl ester (FDME) starting from galactaric acid through dimethyl carbonate (DMC) chemistry. Both sulfonic resins and an iron-based Lewis acid showed to promote the one-pot formation of FDME. The pure product was isolated as a white crystalline solid without the aid of any chromatographic techniques with an isolated yield up to 70 %. Finally, on the basis of the different intermediates identified, a possible reaction mechanism was proposed, which highlights the essential contribute of DMC in the product formation