Sintesi e caratterizzazione di prepolimeri per resine epossidiche derivanti da fonti rinnovabili e naturali attraverso un processo a basso impatto ambientale

La sostituzione di materie prime provenienti da risorse fossili con biomasse rinnovabili, utilizzando un processo a basso impatto ambientale, è una delle più importanti sfide della "Green Chemistry". Allo stesso tempo, la sintesi di resine epossidiche fornisce la chiave per la realizzazione di materiali ad alto valore aggiunto. Tuttavia, ad oggi, il 90% della produzione di resine epossidiche è basato sull'uso di bisfenolo A, che ha effetti di xenoestrogeno, ed epicloridrina, tossica e cancerogena. Su queste basi, è stata individuata una strategia sintetica per la sintesi di prepolimeri innovativi per resine epossidiche, che utilizza come substrato di reazione diidrossibenzeni di origine naturale ed evita l'uso di epicloridrina e altri reagenti tossici o pericolosi. La suddetta strategia sintetica è basata sulla sequenza: allilazione dei diidrossibenzeni - epossidazione dei doppi legami ottenuti. In questa procedura non vengono utilizzati drastiche condizioni di reazione e il solvente è acqua, con una catalisi di trasferimento di fase o, in aggiunte di acetonitrile, in un sistema bifasico. La resa complessiva dei due “step” dipende dalla posizione dei due ossidrili nei diidrossibenzeni. Il reagente che porta la resa massima è l’idrochinone (1,4 diidrossibenzene), che, come riportato in letteratura, permette la formazione di resine epossidiche con proprietà simili alle resine di epicloridrina e bisfenolo A. The substitution of raw materials from fossil fuels with renewable biomass using a low environmental impact process is one of the greatest challenges of the "Green Chemistry". At the same time, the synthesis of epoxy resins provides the key to the realization of high added value materials. However, 90% of the production of epoxy resins is based on the use of bisphenol A, a xenoestrogen, and epichlorohydrin, that is toxic and carcinogenic. On these bases, a synthetic strategy for the synthesis of innovative prepolymers of epoxy resins, that uses dihydroxybenzenes of natural origin as reaction substrates and avoids the use of epichlorohydrin and other toxic or dangerous reagents has been identified. The above synthetic strategy is based on the sequence: allylation of dihydroxybenzenes - epoxidation of the double bonds obtained. In this procedure, drastic reaction conditions are dismissed and the solvent used is water with a phase transfer catalysis or, in addition, acetonitrile in a biphasic system. The overall yield of the two steps depends on the position of the two hydroxyls of the dihydroxybenzenes. The reagent that leads to the highest yield is hydroquinone (1,4 dihydroxybenzene), which, as reported in literature, allows the formation of epoxy resins with similar properties to the resins from bisphenol A and epichlorohydrin.

Reações de sulfanilação pela catálise por transferência de fase de algumas 2-sulfinilciclanonas, racêmicas e opticamente ativas, empregando catalisador não quirálico e alguns quirálicos

A presente tese trata das reações de sulfanilação de algumas 2-sulfinilciclanonas racêmicas pelo método de catálise por transferência de fase (CTF), seja usando cloreto de benziltrietilamônio (TEBAC) seja usando catalisador quirálico. As reações de sulfanilação pelo método de CTF empregando TEBAC, forneceram produtos sulfanilados em altos rendimentos (75-93%), enquanto que as reações empregando a mesma metodologia, utilizando catalisadores quirálicos, conduziram não só a altos rendimentos, mas também a um aumento no excesso diastereomérico. Foram determinadas as configurações relativas da 2metilsulfanil- 2-metilsulfinilciclopentanona e 2-p-tolilsulfanil-2metilsulfinilcicloexanona pela análise de difração de Raios-X como sendo 2S*SS*. A parte final da Tese contém reações de sulfanilação da 2-metilsulfinilciclopentanona e 2-metilsulfinilcicloexanona opticamente ativas. É digno de nota que estas, ao contrário da 2-p-tolilsulfinil ciclanonas, descritas na literatura, conduziram a produtos sulfanilados estáveis. Finalmente, a tese mostra um exemplo de condensação aldólica assimétrica partindo da 2-metilsulfanil-2-metilsulfinilcicloexanona opticamente ativa. Com base no conhecimento da configuração deste último composto, foi possível esclarecer o mecanismo da indução assimétrica.

Enantioselective alkylation of β-keto esters promoted by dimeric Cinchona-derived ammonium salts as recoverable organocatalysts

Dimeric anthracenyldimethyl-derived Cinchona ammonium salts are used as chiral organocatalysts in 5 mol% for the phase-transfer enantioselective alkylation reaction of 2-alkoxycarbonyl-1-indanones with activated bromides. The corresponding adducts bearing a new all-carbon quaternary center are obtained usually in high yield and with moderate and opposite enantioselectivity (up to 55%) when using ammonium salts derived from quinidine and its pseudoenantiomer quinine as organocatalysts. These catalysts can be almost quantitatively recovered by precipitation in ether and reused.

Studies in organobismuth chemistry

Perturbations in the bismuth market resulted in Mining and Chemical Products Ltd., seeking further outlets in the market. Together with Manchem Ltd. they were anxious to evaluate the possibility of using bismuth compounds as a replacement for lead/calcium soaps in paint driers. A range of new organobismuth compounds were synthesised of the type RBiX2 and R3BiX2 (X= halogen, OOCR, dithiocarbamate). A variety of synthetic techniques were explored, including the use of mathematical reactions, phase-transfer catalysis and microwave energy. The preparation of a range of trivalent and pentavalent organobismuth carboxylates is reported and their infra-red , 13C, lH nmr spectra. The compounds were evaluated as paint driers and in cases found to enhance paint drying to a greater degree than the standard driers, to which they were being compared. The drying times of paint films containing the organobismuth compounds are reported, together with a comparison of the drying times with the addition of bismuth tris-diethyldithiocarbamate, which may promote the cross-linking reaction that occur in paint films during the drying process. Examples are reported to illustrate the great reductions in reaction times possible when using microwave energy. Reactions such as metallation of aromatic rings, ligand redistribution and synthesis were carried out in PTFE containers in a conventional domestic microwave oven. An X-ray diffraction study of (phenylazophenyl-C,N')mercury(II) chloride has shown it to be dimeric via long Hg-Cl bridging interactions of 3.367A. Its crystal structure is reported, together with its 13C nmr spectra and mass spectrum. The Lewis acidity of compounds of the type RBiX2 was investigated. The donor group being anchored to the organo group (R). The dithiocarbamates bis- (diethyldithiobarbamato)phenylbismuth(Ill) and [2-2-pyridyl)phenylbismuth(III) were synthesised, and their crystal structures, 14N, 13C nmr ar1d infra-red spectra are reported. Both compounds are pseudo-pentagonal bipyramidal in geometry, with two long Bi-S bonds and two short Bi-S bonds. The reaction of RBiBr2 (R= 2-(pyridyl) with various ligands is reported. The infra-red evidence suggesting that the coordination of extra ligands is accompanied by a reduction of the strength of the Bi-interaction.

Sintesi e caratterizzazione strutturale di derivati piperidinici e morfolinici chirali

The topic of this thesis concerns the study of catalytic processes for the synthesis of chiral 3,4,5-trisubstituted piperidine and 2,6-disubstituted morpholine. Substrates possessing an α,β-unsaturated ester and a ketone moiety, able to undergo addition/cyclization cascade reactions with different pro-nucleophiles (thiophenols, acetone cyanohydrin and malononitrile), have been evaluated. Chiral and achiral systems for phase-transfer catalysis have been applied as catalysts. Moderate enantiomeric excesses have been obtained for the morpholinic products and good to excellent values for the piperidinic products, by using cyclopeptoids and quaternary ammonium salts derived from Chincona alkaloids as catalysts respectively. Moreover, the absolute configuration of the 3,4,5-trisubstituted piperidines has been determined through quantomechanical simulations of their chirooptical spectra. Finally, the relative configuration of the 2,6-disubstituted morpholines has been assigned through NMR experiments.

New methodologies in organocatalysis: from discovery to application and mechanistic

This PhD thesis deals with three different topics: i) sulfoxonium ylides, ii) donor-acceptor cyclopropanes, and iii) desymmetrization reactions. Catalysis, and in more detail organocatalysis, is the fil rouge linking the three subjects of study. The main focus treated during this doctorate period is the reactivity of sulfoxonium ylides, and in particular stabilized sulfoxonium ylides. Special attention has been dedicated to the behavior of these particular substrates under asymmetric and non-asymmetric reaction conditions. Moreover, also similarities and differences with the related, less stable, sulfonium ylides were fully analyzed, both experimentally and from a theoretical point of view. Two different reactions were developed in full. One conducted under acidic reaction conditions and the second one exploiting the asymmetric aminocatalysis. Subsequently, the reactivity of donor-acceptor cyclopropanes was studied. After different attempts in the development of a new catalytic methodology based on these substrates, a non-conventional reactivity conducted under phase transfer catalysis was discovered and optimized. In particular, a chemodivergent reaction depending on the reaction conditions was developed. Finally, during the period spent abroad, a preliminary study of a desymmetrization reaction was carried out. The studied reaction is based on an asymmetric elimination reaction conducted under asymmetric phosphoric acid catalysis. In summary, this PhD thesis shows the versatility of different organocatalytic methodologies when applied to different reactions and substrates.

Computational investigation of a stereoselective synthesis of atropisomeric hydrazides possessing an N–N stereogenic axis

Axially chiral substrates are an interesting and widely studied class of compounds as they can be found in bioactive natural products and are employed as functional materials or as ligands in asymmetric catalytic processes. One branch of this family is the well-known world of the atropisomers. Among them, atropisomeric compounds possessing an N–N stereogenic axis are one truthfully fascinating system but not completely understood yet. In this thesis, we computationally investigated the mechanism of the diastereoselective formation of the N – N chiral axis of a hydrazide under asymmetric phase transfer catalytic conditions. Moreover, during this study, torsional barriers have been calculated for both the reagent and the product at the density functional theory (DFT). These values turned out to suitably match the experimental values and observations. Finally, Electronic Circular Dichroism (ECD) spectra have been simulated in order to assign the chiral absolute configuration to the products.

Tetra-crowned porphyrin as P450 biomimetic model for carbamazepine oxidation

A substituted porphyrin bearing four crown ether units, H(2)(TCP), was synthesized from the reaction between (5,10,15,20-tetra(o-aminophenyl) porphyrin) and the acyl derivative of the ether (4-carboxy-18-crown-6). The free-base porphyrin was characterized by C, N, and H elemental analysis; UV-vis and IR spectroscopies; and (1)H NMR. The corresponding ironporphyrin, Fe(TCP)Cl, was obtained via iron insertion into H(2)(TCP). Fe(TCP)Cl was employed as catalyst for carbamazepine (CBZ) oxidation by iodosylbenzene (PhIO), 3-chloroperoxybenzoic acid (m-CPBA) or sodium hypochlorite (NaOCl), in methanol or in a biphasic water/dichloroethane system. The crowned ironporphyrin proved to be a highly efficient and selective catalyst for CBZ epoxidation even in the biphasic dichloroethane /H(2)O system, with no need for an additional phase transfer agent.

Jacobsen catalyst immobilized on chitosan membrane as interface catalyst in organic/aqueous system for alkene oxidation

The Jacobsen catalyst, Mn(salen), was immobilized in chitosan membrane. The obtained Mn(salen)-Chit was characterized by thermogravimetric analysis (TC), differential thermal analysis (DTA), differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), degree of N-acetylation by (1)H NMR, and UV-vis spectroscopy. The UV-vis absorption spectrum of the encapsulated catalyst displayed the typical bands of the Jacobsen catalyst, and the FT-IR presented an absorption band characteristic of the imines present in the Jacobsen catalyst. The chitosan membranes were available, in a biphasic system, as a catalytic barrier between two different phases: an organic substrate phase (cyclooctene or styrene) and an aqueous solution of either m-CPBA, t-BuOOH or H(2)O(2), and dismissing the need for phase transfer agents and leading to better product yields compared with the catalyst in homogeneous medium. This new catalyst did not leach from the support and was reused many times, leading to high turnover frequencies. (C) 2009 Elsevier B.V. All rights reserved.

Organocatalytic tandem reactions of polyfunctional compounds for the synthesis of enantioenriched heterocycles. Reazioni tandem organocatalitiche di composti polifunzionali per la sintesi di eterocicli enantioarricchiti.

In questo lavoro di tesi sono state sviluppate reazioni domino, tandem e procedure one-pot per ottenere eterocicli enatioarricchiti. Lo sviluppo di queste metodologie sintetiche è molto importante perché permettono di ottenere molecole complesse partendo da prodotti semplici, senza effettuare ripetuti passaggi di purificazione (stop-and-go or step-by-step synthesis). Lo scopo di questo lavoro è di ottenere derivati tetraidrofuranici modificati e derivati ossoazzolinici enantioarrichiti tramite reazioni SN2-Michael o tramite reazioni aldolica-ciclizzazione-Michael usando la catalisi asimmetrica a trasferimento di fase (PTC). Come catalizzatori PTC per imprimere enantioselezione sono stati utilizzati sali di ammonio quaternario derivati dagli alcaloidi della Cinchona. Sono state ottimizzate le condizioni di reazione (base inorganica, temperatura, solvente, tempo di reazione) per i diversi substrati presi in considerazione. I prodotti target sono stati ottenuti con buone rese, ottime diastereoselezioni ma con bassa enantioselezione. I risultati ottenuti richiedono un’ulteriore ottimizzazione e dovranno essere valutate variazioni strutturali dei nucleofili utilizzati. In this thesis were developed domino, tandem reactions and one-pot procedures to obtained enantioenriched heterocycles. The development of these methodologies is very fundamental because they allow to obtain complex molecules starting from raw materials, without carrying out repeated purification steps (stop-and-go or step-by-step synthesis). The purpose of this work is to obtain enantioenriched tetrahydrofuran and oxazoline derivatives through a SN2-Michael reaction or a aldol- cyclization-Michael reaction using the phase-transfer asymmetric catalysis (PTC). For imprint enantioselection we used Cinchona alkaloids quaternary ammonium salts derivatives. The reaction conditions (inorganic base, temperature, solvent, reaction time) were optimised for the different substrates taken into account. The target products were obtained with good yields, excellent diastereoselections but with low enantioselections. The obtained results require further optimization and structural changes in the nucleophiles used must be evaluated.

Enantioselective Reactions Promoted by Organocatalytic Species From The Natural Chiral Pool

During the course of my Ph.D. in the laboratories directed by Prof. Alfredo Ricci at the Department of Organic Chemistry “A. Mangini” of the University of Bologna, I was involved in the study and the application of a number of organocatalytic systems, all coming from the natural chiral pool. The first part of this thesis will be devoted to new homogeneous organocatalytic reactions promoted by Cinchona alkaloid-based organocatalysts. Quinine based catalysts were found to be a very effective catalyst for Diels-Alder reactions involving 3-vinylindoles. Excellent results in terms of yields and enantioselectivities were achieved, outlining also a remarkable organocatalytic operational mode mimicking enzymatic catalysis. The same reaction with 2-vinylindoles showed a completely different behaviour resulting in an unusual resolution-type process. The asymmetric formal [3+2] cycloaddition with in situ generated N-carbamoyl nitrones using Cinchona-derived quaternary ammonium salts as versatile catalysts under phase transfer conditions, outlines another application in organocatalysis of this class of alkaloids. During the seven months stage in the Prof. Helma Wennemers’ group at the Department of Chemistry of the University of Basel (Switzerland) I have been involved in organocatalysis promoted by oligopeptides. My contribution regarded the 1,4-addition reaction of aldehydes to nitroolefins. In the work performed at the Department of Organic Chemistry “A. Mangini” of the University of Bologna, in collaboration with the ‘Institut Charles Gerhardt-Montpellier, of Montpellier (France) the possibility of performing for the first time heterogeneous organocatalysis by using a natural polysaccharide biopolymer as the source of chirality was disclosed. With chitosan, derived from deacetylation of chitin, a highly enantioselective heterogeneous organocatalytic aldol reaction could be performed. The use of an eco-friendly medium such as water, the recyclability of the catalytic specie and the renewable nature of the polysaccharide are assets of this new approach in organocatalysis and open interesting perspectives for the use of biopolymers.

Using sulfur isotope fractionation to understand the atmospheric oxidation of SO 2

Sulfate aerosol plays an important but uncertain role in cloud formation and radiative forcing of the climate, and is also important for acid deposition and human health. The oxidation of SO2 to sulfate is a key reaction in determining the impact of sulfate in the environment through its effect on aerosol size distribution and composition. This thesis presents a laboratory investigation of sulfur isotope fractionation during SO2 oxidation by the most important gas-phase and heterogeneous pathways occurring in the atmosphere. The fractionation factors are then used to examine the role of sulfate formation in cloud processing of aerosol particles during the HCCT campaign in Thuringia, central Germany. The fractionation factor for the oxidation of SO2 by ·OH radicals was measured by reacting SO2 gas, with a known initial isotopic composition, with ·OH radicals generated from the photolysis of water at -25, 0, 19 and 40°C (Chapter 2). The product sulfate and the residual SO2 were collected as BaSO4 and the sulfur isotopic compositions measured with the Cameca NanoSIMS 50. The measured fractionation factor for 34S/32S during gas phase oxidation is αOH = (1.0089 ± 0.0007) − ((4 ± 5) × 10−5 )T (°C). Fractionation during oxidation by major aqueous pathways was measured by bubbling the SO2 gas through a solution of H2 O2

Poly(lactide): from hyperbranched copolyesters to new block copolymers with functional methacrylates

The prologue of this thesis (Chapter 1.0) gives a general overview on lactone based poly(ester) chemistry with a focus on advanced synthetic strategies for ring-opening polymerization, including the emerging field of organo catalysis. This section is followed by a presentation of the state-of the art regarding the two central fields of the thesis: (i) polyfunctional and branched poly(ester)s in Chapter 1.1 as well as (ii) the development of new poly(ester) based block copolymers with functional methacrylates (Chapter 1.2). Chapter 2 deals with the synthesis of new, non-linear poly(ester) structures. In Chapter 2.1, the synthesis of poly(lactide)-based multiarm stars, prepared via a grafting-from method, is described. The hyperbranched poly(ether)-poly(ol) poly(glycerol) is employed as a hydrophilic core molecule. The resulting star block copolymers exhibit potential as phase transfer agents and can stabilize hydrophilic dyes in a hydrophobic environment. In Chapter 2.2, this approach is expanded to poly(glycolide) multiarm star polymers. The problem of the poor solubility of linear poly(glycolide)s in common organic solvents combined with an improvement of the thermal properties has been approached by the reduction of the total chain length. In Chapter 2.3, the first successful synthesis of hyperbranched poly(lactide)s is presented. The ring-opening, multibranching copolymerization of lactide with the “inimer” 5HDON (a hydroxyl-functional lactone monomer) was carefully examined. Besides a precise molecular characterization involving the determination of the degree of branching, we were able to put forward a reaction model for the formation of branching during polymerization. Several innovative approaches to amphiphilic poly(ester)/poly(methacrylate)-based block copolymers are presented in the third part of the thesis (Chapter 3). Block copolymer build-up especially relies on the combination of ring-opening and living radical polymerization. Atom transfer radical polymerization has been successfully combined with lactide ring-opening, using a “double headed” initiator. This strategy allowed for the realization of poly(lactide)-block-poly(2-hydroxyethyl methacrylate) copolymers, which represent promising materials for tissue engineering scaffolds with anti-fouling properties (Chapter 3.1). The two-step/one-pot approach forgoes the use of protecting groups for HEMA by a careful selection of the reaction conditions. A series of potentially biocompatible and partially biodegradable homo- and block copolymers is described in Chapter 3.2. In order to create a block copolymer with a comparably strong hydrophilic character, a new acetal-protected glycerol monomethacrylate monomer (cis-1,3- benzylidene glycerol methacrylate/BGMA) was designed. The hydrophobic poly(BGMA) could be readily transformed into the hydrophilic and water-soluble poly(iso-glycerol methacrylate) (PIGMA) by mild acidic hydrolysis. Block copolymers of PIGMA and poly(lactide) exhibited interesting spherical aggregates in aqueous environment which could be significantly influenced by variation of the poly(lactide)s stereo-structure. In Chapter 3.3, pH-sensitive poly(ethylene glycol)-b-PBGMA copolymers are described. At slightly acidic pH values (pH 4/37°C), they decompose due to a polarity change of the BGMA block caused by progressing acetal cleavage. This stimuli-responsive behavior renders the system highly attractive for the targeted delivery of anti-cancer drugs. In Chapter 3.4, which was realized in cooperation, the concept of biocompatible, amphiphilic poly(lactide) based polymer drug conjugates, was pursued. This was accomplished in the form of fluorescently labeled poly(HPMA)-b-poly(lactide) copolymers. Fluorescence correlation spectroscopy (FCS) of partially biodegradable block copolymer aggregates exhibited fast cellular uptake by human cervix adenocarcinoma cells without showing toxic effects in the examined concentration range (Chapter 4.1). The current state of further projects which will be pursued in future studies is addressed in Chapter 4. This covers the synthesis of biocompatible star block copolymers (Chapter 4.2) and the development of new methacrylate monomers for biomedical applications (Chapters 4.3 and 4.4). Finally, the further investigation of hydroxyl-functional lactones and carbonates which are promising candidates for the synthesis of new hydrophilic linear or hyperbranched biopolymers, is addressed in Chapter 4.5.

Synthesis, reactivity and applications of 3,5-dimethyl-4-nitroisoxazole derivatives

3,5-dimethyl-4-nitroisoxazole derivatives are useful synthetic intermediates as the isoxazole nucleus chemically behaves as an ester, but establish better-defined interactions with chiral catalysts and lability of its N-O aromatic bond can unveil other groups such as 1,3-dicarbonyl compounds or carboxylic acids. In the present work, these features are employed in a 3,5-dimethyl-4-nitroisoxazole based synthesis of the γ-amino acid pregabalin, a medication for the treatment of epilepsy and neuropatic pain, in which this moiety is fundamental for the enantioselective formation of a chiral center by interaction with doubly-quaternized cinchona phase-transfer catalysts, whose ability of asymmetric induction will be investigated. Influence of this group in cinchona-derivatives catalysed stereoselective addition and Darzens reaction of a mono-chlorinated 3,5-dimethyl-4-nitroisoxazole and benzaldehyde will also be investigated.

Stereoselective synthesis of the dolastatin units by organotrifluoroborates additions to alpha-amino aldehydes

Dolastatin units were synthesized from the 1,2-addition reactions of potassium allyl or crotyltrifluoroborate salts to aldehyde derivatives from natural amino acids. The reactions were carried out in presence of a phase-transfer catalyst in a biphasic medium at room temperature and excellent yields (>89-93%) and stereoselective (>90:10 to 98:2) were obtained. The dolastatin units 8 and 14a-b were obtained after three steps in good overall yields (50-62%). (C) 2007 Elsevier Ltd. All rights reserved.