L'utilizzo di carbonati come reagenti per la sintesi "green" di derivati fenolici: l'esempio del 2-fenossi-1-etanolo

2-Phenoxyethanol (ethylene glycol monophenyl ether) is used as solvent for cellulose acetate, dyes, inks, and resins; it is a synthetic intermediate in the production of plasticizers, pharmaceuticals, and fragrances. Phenoxyethanol is obtained industrially by reaction of phenol with ethylene oxide, in the presence of an homogeneous alkaline catalyst, typically sodium hydroxide. The yield is not higher than 95-96%, because of the formation of polyethoxylated compounds. However, the product obtained may not be acceptable for use in cosmetic preparations and fragrance formulations, due to presence of a pungent “metallic” odor which masks the pleasant odor of the ether, deriving from residual traces of the metallic catalyst. Here we report a study aimed at using ethylene carbonate in place of ethylene oxide as the reactant for phenoxyethanol synthesis; the use of carbonates as green nucleophilic reactants is an important issue in the context of a modern and sustainable chemical industry. Moreover, in the aim of developing a process which might adhere the principles of Green Chemistry, we avoided the use of solvents, and used heterogeneous basic catalysts. We carried out the reaction by using various molar ratios between phenol and ethylene carbonate, at temperatures ranging between 180 and 240°C, with a Na-mordenite catalyst. Under specific conditions, it was possible to obtain total phenol conversion with >99% yield to phenoxyethanol in few hours reaction time, using a moderate excess of ethylene carbonate. Similar results, but with longer reaction times, were obtained using a stoichiometric feed ratio of reactants. One important issue of the research was finding conditions under which the leaching of Na was avoided, and the catalyst could be separated and reused for several reaction batches.

Parametric Sensitivity Analysis of the Most Recent Computational Models of Rabbit Cardiac Pacemaking

The cellular basis of cardiac pacemaking activity, and specifically the quantitative contributions of particular mechanisms, is still debated. Reliable computational models of sinoatrial nodal (SAN) cells may provide mechanistic insights, but competing models are built from different data sets and with different underlying assumptions. To understand quantitative differences between alternative models, we performed thorough parameter sensitivity analyses of the SAN models of Maltsev & Lakatta (2009) and Severi et al (2012). Model parameters were randomized to generate a population of cell models with different properties, simulations performed with each set of random parameters generated 14 quantitative outputs that characterized cellular activity, and regression methods were used to analyze the population behavior. Clear differences between the two models were observed at every step of the analysis. Specifically: (1) SR Ca2+ pump activity had a greater effect on SAN cell cycle length (CL) in the Maltsev model; (2) conversely, parameters describing the funny current (If) had a greater effect on CL in the Severi model; (3) changes in rapid delayed rectifier conductance (GKr) had opposite effects on action potential amplitude in the two models; (4) within the population, a greater percentage of model cells failed to exhibit action potentials in the Maltsev model (27%) compared with the Severi model (7%), implying greater robustness in the latter; (5) confirming this initial impression, bifurcation analyses indicated that smaller relative changes in GKr or Na+-K+ pump activity led to failed action potentials in the Maltsev model. Overall, the results suggest experimental tests that can distinguish between models and alternative hypotheses, and the analysis offers strategies for developing anti-arrhythmic pharmaceuticals by predicting their effect on the pacemaking activity.

Effetto dei farmaci presenti in ambiente sulle larve di orata (Sparus aurata)

La presenza di residui dei farmaci ad uso umano e veterinario nelle acque superficiali è in costante aumento a causa del loro elevato consumo. L’impatto ambientale dei prodotti farmaceutici è riconosciuto in tutto il mondo ma attualmente ancora non sono presenti degli Standard di qualità ambientale per queste sostanze in ambiente acquatico. L’agenzia europea per i farmaci (EMEA) ha introdotto delle linee guida per la valutazione del rischio ambientale per tutti i nuovi farmaci prima di provvedere alla registrazione, ma in nessun caso la loro autorizzazione in commercio è vietata. Una volta assunti, i farmaci sono escreti dagli organismi in forma nativa o come metaboliti, e attraverso gli scarichi urbani raggiungono i depuratori che li rimuovono solo in parte. Di conseguenza, i residui dei farmaci vengono ritrovati nei fiumi, nei laghi, fino alle acque marine costiere. Anche se presenti a basse concentrazioni (ng-μg/L) nelle acque superficiali, i farmaci possono provocare effetti avversi negli organismi acquatici. Queste specie rappresentano involontari bersagli. Tuttavia molti di essi possiedono molecole target simili a quelle dell’uomo, con i quali i farmaci interagiscono per indurre gli effetti terapeutici; in questo caso i farmaci ambientali possono causare effetti specifici ma indesiderati sulla fisiologia degli animali acquatici. Le interazioni possono essere anche non specifiche perché dovute agli effetti collaterali dei farmaci, ad esempio effetti ossidativi, con potenziali conseguenze negative su vertebrati ed invertebrati. In questo lavoro sono stati valutati i potenziali effetti indotti nelle larve di orata da quattro classi di farmaci ovvero: carbamazepina (antiepilettico), ibuprofene (antinfiammatorio non steroideo), caffeina (stimolante) e novobiocina (antibiotico). In particolare, in questo lavoro si è valutato inizialmente il tasso di sopravvivenza delle larve di orata esposte ai farmaci, per verificare se l’esposizione determinasse effetti di tossicità acuta; successivamente si è passati alla valutazione di due biomarker : il danno al DNA e la perossidazione lipidica per verificare la presenza di effetti tossici sub-letali. Le larve sono state esposte per 96 ore alle concentrazioni di 0.1, 1 (MEC), 10 e 50 µg/L (>MEC) di carbamazepina e novobiocina, a 0.1, 5 (MEC),10 e 50 µg/L (> MEC) di ibuprofene ed a 0.1, 5 (MEC),15 e 50 µg/L (> MEC) di caffeina, rappresentative delle concentrazioni riscontrate in ambiente acquatico e al di sopra di quest’ultimo. L’analisi dei dati sulla sopravvivenza ha dimostrato che la carbamazepina, l’ibuprofene, la novobiocina e la caffeina non hanno effetti significativi alle concentrazioni testate. La valutazione dei biomarker ha evidenziato un generale decremento significativo dei livelli di danno primario al DNA e per la perossidazione lipidica è stato generalmente osservato un decremento alle dosi dei farmaci più basse, seguito da un aumento a quelle più elevate. Nell’insieme i dati indicano che alle concentrazioni testate, i farmaci carbamazepina, caffeina, ibuprofene e novobiocina non hanno prodotto alterazioni attribuibili alla comparsa di effetti avversi nelle larve di S. aurata dopo 96 ore di esposizione.

Studio della reattività del glicerol carbonato nella sintesi di derivati fenolici

Supported by the increasing sustainable awareness, glycerol carbonate has gained much interest over the last 20 years because of its versatile reactivity and as a way to valorize waste glycerol. Numerous synthesis pathways for this molecule were identified, some of them very promising and on the verge of being applied at an industrial scale. Here, we report a study aimed at valorizing glycerol carbonate as chemical intermediate, in order to synthesize 2-hydroxymethyl-1,4-benzodioxane (HMB). This molecule finds important applications as key intermediate for the synthesis of a broad class of pharmaceuticals and therapeutic agents. Concerning the presence of a stereogenic center on the hydroxymethyl group, due to the pharmaceutical importance to obtain and isolate one single enantiomer, , nowadays HMB is obtained through batch scale process, using a multi-reaction approach and starting from reagents of the chiral pool. We carried out the reaction from a solution of glycerol carbonate and catechol 2:1. In the presence of a simple basic catalyst, at high temperatures, it was possible obtain total reactants conversion and high yield to HMB in few hours reaction time. Also, in the aim of developing a process which might adhere the principles of Green Chemistry, we avoided the use of solvents. Similar results were obtained using a 1:1 feed ratio of reactants, even if selectivity to HMB decrease, due to the presence of side reactions. A complete study of the reaction mechanism is proposed in this thesis.