Preparation, Structure, and Reactivity of the First Bicyclic Benziodazole and its Monocyclic Analogue

University of Minnesota M.S. thesis. August 2019. Major: Chemistry. Advisor: Viktor Zhdankin. 1 computer file (PDF); x, 125 pages.Nitrogen containing mono-heterocyclic hypervalent iodine(III) compounds, benziodazoles, have been investigated by several research groups as well as ours. These compounds are commonly used as efficient oxidative reagents for various organic substrates. The preparation, structure, and reactivity of the first bicyclic benziodazole compound, N,N’-diisopropylbenziodazole, will be reported and compared to the monocyclic N-isopropyl-m-chlorobenzoate benziodazole. Both benziodazoles were prepared by the m-chloroperoxybenzoic acid oxidation of 2-iodo-N-isopropylbenzamide or 2-iodo-N,N'-diisiopropylisophthalamide, respectively, and their structures were established by X-ray crystallography. These benziodazoles were investigated as efficient reagents for oxidatively assisted coupling reactions to form esters and amides

Teaching Crossroads: 10th IPB Erasmus Week

This is the fourth number of a project which started in 2011 when the idea of publishing the lectures delivered by guest teachers in our Erasmus Week came up. This annual event is organised by the Polytechnic Institute of Bragança (IPB) and takes place normally in the beginning of May. The title was not difficult to find as the main purpose with this publication was to include every research and teaching areas fitting a multidisciplinary journal with a very specific European approach, however centred in Portugal, at the IPB. Therefore Teaching Crossroads was born aiming at reaching the largest number of readers within both the Portuguese and the international academic community. In the first three years of publication, we published more than 30 articles including areas as different as business sciences and law, agricultural sciences and natural resources, chemistry, multimedia, tourism, nursing and health care, economics, education, information technology and applied sciences, but yet so far-reaching. Always intending to improve the quality and rigour of this journal, the two last numbers have already been peer-reviewed. This is now the number regarding the 10th Erasmus Week that took place in May 2014. This year, the focus of our attention is placed on Education and Chemistry. Concerning the whole publication, we present you with a brief description of each article. Astrid Ebenberger focuses on the Austrian Educational system, demonstrating how it has been influenced by early 20th century pedagogues, namely Ellen Key, Maria Montessori and Helen Parkhurst, whose ideas and actions became paramount in the transformation of the educational system in Austria. The author also puts forth an outline of further developments of teacher education, drawing some critical guidelines regarding the sustainability of the Austrian education system in the future. Cláudia Martins, who lectures a seminar on the Portuguese language and culture to the guest teaching and non-teaching staff during our Erasmus Weeks, enlightens us about cognitive linguistics, particularly focusing on figurative language and tropes. Metaphors are here the crux of the matter and the author shows how they are omnipresent in languages in our daily lives. That is, one needs to understand metaphors as conceptual sources that reveal crucial for the understanding of the semantic meaning of both synchronic and diachronic cultural and social categories and concepts that define human experience and therefore language. The author focuses on the area of Portuguese food expressions serving us delightful metaphors, getting our taste buds tingling at the Portuguese language and culture. Kamil Mielnik gives us an account of the Polish gymnasium, 3rd Cycle of Basic Education or junior high school, for pupils aged 13 to 16, with regard to the Common European Framework of Reference for Languages (CEFR), while he also describes formative assessment and its features, as well as the European Language Portfolio, explaining ultimately how the latter can strongly support self-regulated learning in Polish Gymnasium. Katarzyna Morena deals with a very common problem as far as learning a new language is concerned, that is language anxiety. The author focuses on the speaking skill by highlighting problems and effects associated with speaking in front of the others, either in a formal or informal context. In the study the author carried out, some strategies are presented so that teachers can teach their students how to overcome anxiety problems. Elżbieta Wojaczyńska demonstrates in her article how the area of organic chemistry can appear to be fairly pertinent in our daily lives be it, for instance, on pharmaceutical, cosmetic, or agrochemical industries. Even though we’re not aware of it or never question the existence of the product compounds, this is of the utmost importance for health issues. Therefore, the author focuses on the methods of preparation of nonracemic sulfoxides and examples of their various applications in asymmetric synthesis as chiral substrates and inducers, organocatalysts or in complexes with different metals. We would like to seize the opportunity to thank all the contributors that so far have participated in the consolidation of Teaching Crossroads, namely authors and reviewers. It is also worth mentioning the helpful and valuable work of Soraia Maduro, the designer of the most appealing and well-adjusted cover, and Atilano Suarez who sets the book layout in a very perfectionist way. Being all said, we are once more proud of making interesting and relevant studies available to the academic community, not only to the IPB, but also to the rest of the European and other international universities, IPB partners in the educational promotion and cooperation. Therefore, we wish you a very enjoyable and meaningful readin

Synthesis and reactivity of aryl iodo difluorides

Organofluorine substrates are molecules of increasing demand in both academic and industrial settings. Organofluorine compounds are very rare in nature and therefore several approaches to their synthesis have been developed. In the work performed during this research tenure, the approach towards the synthesis of organofluorine substrates is based on the use of hypervalent iodine reagents. The structure of the research program can be summarized into three main sections: Synthesis of aryl iodo difluorides; Reactivity of aryl iodo difluorides towards organoselenium substrates; Approach toward stereoselective fluorinations with the synthesis of chiral iodo difluorides. Aryl iodo difluorides reagents have been known for more than a century but they have not been extensively used mainly due to their difficulty of synthesis, which require harmful and hazardous reagents. We have developed an alternative method for their preparation involving three synthetic steps: perborate oxidation of an aryl iodide, followed by basic hydrolysis and subsequent treatment with hydrofluoric acid. A number of aryl iodo difluorides were synthesized using this procedure and each of them is characterized by high purity and high yield. The reactivity of (difluoroiodo)toluene (DFIT) as a fluorinating agent was tested on organoselenium substrates. a-Seleno esters, amide and nitriles undergo a-fluorination when treated with 2 equivalents of DFIT. Under these conditions, the monofluoro derivatives were obtained with yields ranging from 20% to 65%. Additionally, (difluoroiodo)toluene can be employed in oxidative fluorinations. The exploitation of its oxidative nature produced tetraethyl ammonium iodo difluoride, and preliminary results indicate that it can be used as fluorinating agent, as well. The third aspect of the research dealt with stereoselective fluorination reactions. The synthesis of an opportune chiral iodo difluoride can provide the further development of hypervalent iodine reagents as fluorinating reagents. Different substrates were used to reach this goal and the study conducted in this direction brought about the synthesis of a difluoride with the iodine atom in oxidation state V, which can be use as chiral fluorine transfer after a simple modification of its structure

Structurally defined α-Tetralol-Based chiral hypervalent iodine reagents

A novel class of chiral hypervalent iodine reagents containing an α-tetralol-scaffold is being introduced. Iodine triacetate is employed in a key-step as highly selective and efficient iodinating reagent for a short and convenient synthesis of iodine(III) derivatives. Solid state X-ray analyses offer valuable structural information while reactivities and stereoselectivities are investigated in three model reactions

The Umpolung Reactivity of Hypervalent Iodine Reagents – Novel Electrophilic Group transfer Reactions

Hypervalent iodine reagents are compounds containing iodine in a higher oxidation state, generally iodine(III) or iodine(V). While iodine(V) compounds are typically oxidation reagents, iodine(III) compounds exhibit reactivity and chemical properties closer to those of transition metal complexes, acting as electrophilic synthons of normally nucleophilic groups. Benziodoxoles and benziodoxolones are cyclic compounds containing an iodine(III) core, which have attracted much interest in the scientific community due to their increased stability when compared to the acyclic analogues, allowing a larger variety of possible chemical transformations. Recently, several new reagents have been synthesized for electrophilic or oxidative atom-transfer reactions. Such is the example of C–C bond formation Togni’s reagents for CF3 transfer or EBX for alkynyl transfer, and C–N bond formation ABX for azide transfer. In this thesis, two new protocols that take advantage of the polarity inversion or umpolung properties of benziodoxolone-derived reagents are disclosed. The first method, a sulfonylation strategy compatible with both aliphatic and aromatic amines proved to be an efficient and versatile method to obtain sulfonamides. The developed strategy consists on the formation of a sulfonyl-bearing benziodoxolone reagent through the reaction between a sulfinate salt and the benziodox-olone precursor, with the subsequent in situ addition of an amine. With this method, 25 sulfona-mide examples were obtained in moderate to quantitative yields, also in a gram scale. In addition, mechanistic studies of this reaction with GC-MS and ESI-MS studies, as well as DFT calculations are disclosed. In the second approach, 4 novel hypervalent iodine reagents bearing transferrable primary amines are described. These reagents were found to be stable and easily isolable compounds, being obtained in excellent to quantitative yields. The application of these reagents in the α-amination of indanone β-ketoesters carbon nucleophiles is also reported, showing compatibility with both electron-withdrawing and donating functional groups. 20 examples of α-aminocarbonyl com-pounds are obtained in up to 83% yield. Crystal structures were obtained for all these reagents, confirming the N–I bond. Likewise, mechanistic studies of this reaction are disclosed, including ESI-MS studies and DFT calculations. The work developed in this thesis constitutes a structural platform for further improvement in the access to bioactive molecules, opening room for further developments in unconventional bond disconnections.Os reagentes de iodo hipervalente são compostos que contém iodo em um estado de oxidação superior, geralmente iodo(III) ou iodo(V). Compostos de iodo(V) são tipicamente reagentes de oxidação, enquanto que os compostos de iodo(III) exibem reatividade e propriedades químicas semelhantes às dos complexos de metais de transição, agindo como sintões eletrofílicos de grupos tipicamente nucleofílicos. Os benziodoxoles e os benziodoxolones são compostos cíclicos que contém um núcleo de iodo(III), tendo estes despoletado bastante interesse na comunidade científica devido a uma estabilidade superior à dos seus análogos acíclicos. Recentemente, diversos novos reagentes foram sintetizados para reações de transferência eletrofílica ou oxidativa de grupos funcionais, como os reagentes para a formação de ligações C–C, por exemplo os reagentes de Togni para transferência de CF3 ou o EBX para transferência de alcinos, e reagentes de formação de ligações C–N, como o ABX para a transferência de azida. Nesta tese, são divulgados dois novos protocolos que utilizam a propriedade de inversão de polaridade ou umpolung de derivados de benziodoxolone. O primeiro método, uma estratégia de sulfonilação compatível com aminas alifáticas e aromáticas, revelou ser um método eficiente e versátil para a obtenção de sulfonamidas. Esta estratégia consiste na formação de um derivado de benziodoxolone contendo o grupo sulfonilo, através da reação entre um sal sulfinato e o precursor de benziodoxolone, com a posterior adição in situ de uma amina. Com este método, 25 sulfonamidas foram obtidas com rendimentos moderados a quantitativos, também em escala de grama. Estudos mecanísticos desta reação com estudos GC-MS, ESI-MS e cálculos DFT são reportados. Na segunda abordagem, 4 novos reagentes de iodo hipervalente contendo aminas primárias transferíveis são descritos. Estes reagentes mostraram-se compostos estáveis e facilmente isoláveis, sendo obtidos com rendimentos excelentes a quantitativos. A aplicação desses reagentes na α-aminação de β-cetoésteres derivados de indanona, como nucleófilos de carbono, também é relatada, mostrando compatibilidade com grupos funcionais atractores e doadores de eletrões. 20 exemplos de compostos α-carbonilamino foram obtidos até 83% de rendimento. Estruturas cristalográficas foram obtidas para todos estes reagentes, confirmando a ligação N–I. Igualmente, estudos mecanísticos desta reação são divulgados, incluindo estudos ESI-MS e cálculos DFT. O trabalho desenvolvido nesta tese constitui uma plataforma estrutural para futuros acessos a moléculas bioativas, através de desconexões de ligações não convencionais

Metal-free regio- and stereoselective vicinal difunctionalisation of dienyl carbamates

La present tesi doctoral té com a propòsit desenvolupar noves metodologies sintètiques per a la preparació regio- i esteroselectiva de segments tipus 1-amino-2-heteroatom-but-3-en-1,2-diil com a components estructurals recurrents en lípids biològics. La proposta retrosintètica parteix de la formació d’un intermedi clau del tipus vinilaziridina, format a partir de dienols fàcilment disponibles, seguit d’una apertura d’anell amb diferents nucleòfils per a donar lloc a anàlegs d’esfingosina 3-heterosubstituits. Partint d’aquest objectiu, s’ha aconseguit desenvolupar seqüencialment una aziridinació intramolecular de carbamats dienílics sense mediació metàl·lica amb PhIO seguit d’una apertura de l’intermedi cíclic, i la subseqüent resolució cinètica organocatalítica d’oxazolidinones, per a donar lloc a productes 1,2-difuncionalitzats enriquits entantiomèricament. Aquest últims poden ser derivatitzats mitjançant la reacció de metàtesi creuada per donar anàlegs d’esfingosina. Alternativament, l’aziridinació asimètrica de carbamats dienílics en presència de reactius quirals de iode hipervalent ha estat estudiada per a la preparació de compostos oxiaminats veïnals enantioenriquits amb resultats prometedors. L’última part de la present tesi doctoral descriu la recerca duta a terme durant l’estada predoctoral a la UC Berkeley sota la supervisió del Prof. R. Sarpong conduent a la síntesi total d’alcaloides de tipus phlenhernina per a la seva posterior avaluació com a fàrmacs pal·liatius de la malaltia de l’Alzheimer. La proposta retrosintètica concep la formació de l’estructura bicíclica de tipus [3.2.2] a través d’una reacció de Diels-Alder de demanda electrònica inversa. Conseqüentment, es va desenvolupar una metodologia promoguda per l’acció d’un àcid de Lewis per preparar de forma regio- i estereoselectiva diferents estructures bicícliques tipus [3.2.2] utilitzant la piridotropona com a diè en conjunció amb diversos dienòfils electrònicament rics.La presente tesis doctoral tiene como objetivo general el desarrollo de nuevas metodologías sintéticas para la preparación regio- y estereoselectiva de segmentos tipo 1-amino-2-heteroatom-but-3-ene-1,2-diilo como estructura recurrente en varios lípidos existentes en la naturaleza. La estrategia retrosintética se basó en la formación de un intermedio de vinilaziridina a partir de dienoles seguido por la apertura con diferentes nucleófilos para formar análogos de esfingosina con sustituyentes heteroatómicos en la posición 3. Con este objetivo, se ha conseguido desarrollar una aziridinación intramolecular de carbamatos dienílicos sin mediación metálica en presencia de PhIO, seguido por una apertura del intermedio bicíclico junto con la consiguiente resolución cinética organocatalítica de las oxazolidinonas racémicas, para dar lugar a productos 1,2-difuncionalitzados enriquecidos enantioméricamente. Al mismo tiempo, estos últimos pueden ser derivatizados mediante la reacción de metátesis cruzada. Alternativamente, la aziridinación asimétrica de carbamatos dienílicos en presencia de reactivos quirales de yodo hipervalente ha sido estudiada para la preparación de compuestos oxiaminados vecinales enantioenriquecidso con resultados prometedores. La última parte de la presente tesis doctoral describe la investigación llevada a cabo durante una estancia predoctoral en la Universidad de Berkeley bajo la supervisión del Prof. R. Sarpong centrada en la síntesis de alcaloides de phleghenrina para su posterior evaluación como fármacos paliativos contra la enfermedad de Alzheimer. La estrategia retrosintética propuesta se basó en la formación del biciclo[3.2.2]nonano presente en los compuestos de phleghenrina mediante una reacción de Diels-Alder con demanda electrónica inversa. Para ello, se ha desarrollado un nuevo protocolo centrado en la preparación regio- y estereoselectiva de biciclo[3.2.2]nonanos con diferentes sustituyentes usando piridotropona como dieno y varios dienófilos electrónicamente ricos en presencia de un ácido de Lewis.The present PhD work aimed at developing new synthetic methodologies for the regio- and stereoselective preparation of 1-amino-2-heteroatom-but-3-ene-1,2-diyl scaffolds as common structural motifs in relevant lipids occurring in nature. The proposed retrosynthetic pathway involved the formation of a key vinylaziridine intermediate from readily available dienols, followed by ring-opening with different nucleophilic sources to give access to 3-heterosubstituted sphingosine analogues. With this objective in mind, we have developed a sequential metal-free PhIO mediated intramolecular aziridination/ring-opening of dienyl carbamates and subsequent organocatalysed kinetic resolution of racemic oxazolidinone intermediates that gave access to enantioenriched 1,2-difunctionalised products that could be further elaborated via cross-metathesis. Alternatively, the asymmetric aziridination of dienyl carbamate in the presence of chiral hypervalent iodine reagents has been studied for the preparation of vicinal oxyaminated compounds with promising results. In addition, the last part of the present PhD work describes the research carried out during a predoctoral stay at UC Berkeley under the supervision of Prof. R. Sarpong, aiming at the total synthesis of phleghenrine alkaloids for the biological evaluation as palliative drugs for Alzheimer’s disease. The proposed retrosynthetic pathway envisioned the formation of the phleghenrine [3.2.2] bicyclic core via an Inverse-Electron Demand Diels-Alder reaction. Therefore, a Lewis acid-promoted protocol for the regio- and stereoselective preparation of different substituted bicyclo [3.2.2] nonanes using pyridotropone as a diene and a set of electron-rich dienophiles has been developed

New n-type 1H-benzimidazole dopants for organic thermoelectric materials

LAUREA MAGISTRALEI polimeri coniugati ad alta mobilità sono un'alternativa emergente ai semiconduttori inorganici più utilizzati per applicazioni termoelettriche a bassa temperatura. I dispositivi termoelettrici richiedono sia materiali per il trasporto di elettroni (n-drogati) che per il trasporto di lacune (p-drogati), tuttavia il drogaggio di tipo n di materiali organici in genere fatica a raggiungere le prestazioni del drogaggio di tipo p. Uno dei copolimeri più studiati, il naftalene-diimide bitiofene di tipo n poli(N,N'-bis-2-ottildodecilnaftalene-1,4,5,8-bis-dicarbossimmide-2,6-diil-alt-5,5'-2,2'-bitiofene) (PNDI(OD)-2T) è efficacemente n-drogato da derivati benzimidazolici stabili all'aria e processabili in soluzione. I principali problemi che limitano le prestazioni di questi sistemi sono legati alla segregazione di fase osservata all'aumentare della concentrazione di drogante e alla bassa percentuale di molecole di droganti attive nel polimero drogato. Secondo recenti studi, è possibile migliorare la solubilità e l'efficienza di drogaggio dei droganti benzimidazolici di tipo n in PNDI(OD)-2T, eseguendo una corretta funzionalizzazione. In questo lavoro sono stati progettati, sintetizzati e completamente caratterizzati nuovi efficienti derivati benzimidazolici. Questi nuovi droganti sono stati opportunamente funzionalizzati, vale a dire con metili, diisopropili e catene a base di glicole etilenico, con l'obiettivo di modulare meglio i livelli energetici di frontiera dei droganti e ridurre la tendenza alla rottura della morfologia del polimero indotta dal drogaggio. In particolare, sono stati scelti i sostituenti a base isopropilica e glicole etilenica sui benzimidazoli sia per ottenere una migliore miscibilità con il polimero sia per ostacolare l'aggregazione dei droganti nei film polimerici. Il metile sul benzimidazolo porta invece ad un aumento dell'HOMO del drogante. Gli effetti della concentrazione dei droganti, processando il solvente, e della temperatura di rinvenimento sulla conducibilità del polimero drogato sono stati studiati e razionalizzati. Un'impressionante conducibilità elettrica di 4,17×10^(-2) S/cm è stata ottenuta per un film sottile di PNDI(OD)-2T drogato con N,N-bis(propan-2-il)-4-(1,3,5,6-tetrametil-2,3-diidro-1H-1,3-benzodiazol-2-il)anilina (DMe-DiPrBI) da una soluzione di toluene. La caratterizzazione IR ha evidenziato la formazione di polaroni localizzati nell'unità NDI del copolimero e ha confermato l’effetto dannoso della bassa temperatura di rinvenimento. Il miglioramento della conducibilità evidenzia l'efficienza dell'approccio di funzionalizzazione del drogante.High-mobility conjugated polymers are an emerging alternative to the most used inorganic semiconductors for low-temperature thermoelectric applications. Thermoelectric devices require both electron-transport (n-doped) and hole-transport (p-doped) materials, but n-type doping of organic materials typically struggles to achieve the performance of p-type doping. The well-studied n-type naphthalene-diimide bithiophene copolymer poly(N,N’-bis-2-octyldodecylnaphthalene-1,4,5,8-bis-dicarboximide-2,6-diyl-alt-5,5’-2,2’-bithiophene) (PNDI(OD)-2T) is efficiently n-doped by air-stable and solution processable benzimidazole derivatives. The major issues limiting the performance of these systems are related to the phase segregation observed at increasing dopant concentration, and the low percentage of active dopant molecules in the doped polymer. According to recent studies, it is possible to improve the solubility and the doping efficiency of n-type benzimidazole dopants in PNDI(OD)-2T by a proper functionalization. In this work, new efficient benzimidazole derivatives were designed, synthetized, and fully characterized. These new dopants were aptly functionalized, namely with methyls, diisopropyls, and ethylene glycol-based chains, aimed at better modulating the frontier energy levels of the dopants and reducing the doping-induced modification of the polymer morphology. In particular, the isopropyl and glycol-based substituents on the phenyl were chosen to both gain a better miscibility with the polymer and hinder dopant aggregation in polymer films. The methyl onto the benzimidazole turns into an increase of the HOMO of the dopant. The effect of dopant concentration, processing solvent, and annealing temperature on conductivity of the doped polymer has been studied and rationalized. An impressive electrical conductivity of 4,17×10^(-2) S/cm has been obtained for a N,N-bis(propan-2-yl)-4-(1,3,5,6-tetramethyl-2,3-dihydro-1H-1,3-benzodiazol-2-yl)aniline (DMe-DiPrBI)-doped PNDI(OD)-2T thin film from toluene solution. IR characterization evidenced the formation of localized polarons in the NDI unit of the copolymer and confirmed the detrimental effect of low temperature annealing. The improvement in conductivity highlights the efficiency of the dopant functionalization approach

Cyclic Hypervalent Iodine Reagents for Azidation: Safer Reagents and Photoredox-Catalyzed Ring Expansion

Azides are building blocks of increasing importance in synthetic chemistry, chemical biology, and materials science. Azidobenziodoxolone (ABX, Zhdankin reagent) is a valuable azide source, but its safety profile has not been thoroughly established. Herein, we report a safety study of ABX, which shows its hazardous nature. We introduce two derivatives, tBu-ABX and ABZ (azidobenziodazolone), with a better safety profile, and use them in established photoredox- and metal-mediated azidations, and in a new ring-expansion of silylated cyclobutanols to give azidated cyclopentanones

Valorisation of glycerol from bio-diesel waste to high value chemicals

Titolo Tesi "Valorizzazione del glicerolo da scarto del biodiesel a sostanze chimiche ad alto valore aggiunto" Suresh Udhavrao Shisodia, Relatore: Prof. Attilio Citterio. Questa tesi è centrata sullo sviluppo di impieghi alternativi delle principali piattaforme C-3 ottenute da biomasse, cioè glicerolo (anche grezzo) e lattato di etile, allo scopo di generare nuovi prodotti sicuri, polimeri e composti bioattivi, in condizioni il più possibile ecocompatibili. L’obiettivo si inquadra in alcune delle principali problematiche previste per il 21° secolo e specificamente la produzione sostenibile a livello industriale di energia, prodotti chimici e materiali utilizzando biomasse al posto di combustibili fossili. Il glicerolo è un’importante risorsa rinnovabile, il cui interesse è cresciuto parallelamente al crescere della produzione del biodiesel, e pur presentando già ora più di 3000 impieghi industriali diversi, è urgente la sua valorizzazione per coprirne il surplus disponibile sul mercato. Anche il lattato di etile ha assunto un ruolo rilevante come solvente e reagente ecologicamente non tossico. Esso è largamente disponibile a partire dalla piattaforma C-3 più importante l’acido lattico, un metabolita rilevante per la facilità con cui è ottenibile da batteri e cellule vegetali o animali a partire da carboidrati. In questa tesi, il lattato di etile è stato studiato principalmente come solvente “green” per ossidazioni di composti organici con acqua ossigenata, identificando la natura di peracido ecocompatibile di questo sistema in grado di converire solfuri, fosfine e composti carbonilici, rispettivamente a solfossidi, fosfinossidi e esteri. Al contrario, gli studi sul glicerolo sono stati affrontati per controllare la chemo- e regio-selettività delle sostituzioni con nucleofili ossigenati ed azotati al legami C-O, favorite da sostituenti carbonato o da gruppi uscenti OH attivati con elettrofili. Come obiettivo specifico si è indagato l’ambito inesplorato delle policondensazioni regio-selettive di derivati del glicerolo mediante reazioni a cascata e reazioni senza solventi. L’intento era quello di sviluppare oligomeri stereo-ordinati, quali eteri del poliglicerolo, uretani ed altri materiali funzionali. L’indagine è poi stata estesa alla preparazione di derivati semplici contenenti unità ferroceniche o indoliche per testarne l'attività antifungina. Allo scopo si è approfondito il ruolo della catalisi omo- ed eterogenea nella sostituzione elettrofila da parte di cationi stabilizzati ferrocenilmetile e idrossialchile. Gli argomenti specifici studiati si possono così riassumere (sulla base dei capitoli della tesi): Capitolo-1. Sintesi, purificazione, reattività del diglicerolo dicarbonato (DGDC) e sua conversione ad oligomeri e polimeri stereoselettivi. In questo contesto, i seguenti aspetti sono stati studiati ed esplorati: a) sintesi di DGDC da diglicerolo commerciale grezzo mediante reazione di carbonatazione termica o attivata da microonde; b) purificazione degli isomeri d,l- e meso- del DGDC per cristallizzazione; c) idrolisi degli isomeri d,l- e meso-DGDC puri a alfa-digliceroli stereoordinati, d) reazioni di sostituzione nucleofila selettiva al legame CO terminale degli isomeri d,l- e meso-DGDC puri con nucleofili all’azoto e all’ossigeno, e) sintesi selettiva di monomeri e polimeri stereoordinati dagli isomeri puri d,l- e meso-DGDC. In tutti i casi si sono seguite le reazioni mediante varie tecniche analitiche TLC, HPLC, GC-MS o CE, ed i prodotti purificati sono stati separati e purificati mediante cromatografia e/o cristallizzazione e, quindi, caratterizzati tramite 1H-/13C-NMR, IR e LCMS. Per alcuni derivati si è ricorso alla caratterizzazione mediante raggi X a cristallo singolo e ad analisi SEM. Le matrici polimeriche sono state caratterizzate mediante analisi DSC e TGA. Le stesse tecniche di analisi sono state applicate in tutti gli altri ambiti di questa tesi. Capitolo-2. Sintesi a cascata di α-glicerol N-alchilcarbammati. I polidrossiuretani sono composti interessanti per le ampie applicazioni in farmacologia, agricoltura e nell’industria chimica ma hanno il difetto di essere convenzionalmente preparati mediante l'uso di reagenti tossici come isocianati, fosgene, nitroderivati, ecc. L’attuale attenzione per un maggior rispetto della salute e sicurezza degli individui e dell’ambiente impone la revisione di questi processi tradizionali con tecnologie più mature ed ecocompatibili. Un passaggio importante in questo ambito si è avuto con le proposte di sostituzione di questi reagenti con anidride carbonica o carbonati organici, in parte ridimensionate dalla necessità di uso di condizioni drastiche che ne limitano l’impiego a molecole labili o poli-sostituite. Nell’ottica di proporre una soluzione al problema, si è indagato e sviluppato un nuovo ed efficiente percorso di sintesi per la preparazione di molecole bifunzionali e polifunzionali a partire dal glicerolo, carbonati alchilici e ammine in un unico stadio. Si è dimostrato che per questa via sono sintetizzabili con buona selettività gli α-glicerol N-alchilcarbammati. Sono stati studiati i fattori che influenzano la regioselettività alfa/beta della sostituzione e si è accertato il ruolo chiave del carbonato lineare misto intermedio formato in situ per sostituzione selettiva in corrispondenza della posizione terminale del glicerolo. Sono stati inoltre indagati due fenomeni rilevanti per la mono funzionalizzazione selettiva: a) l’equilibrazione dei regioisomeri a favore di quello terminale (alfa) e b) l’inibizione verso ulteriori sostituzioni. L’approccio è estendibile a di- o poli-ammine ottenendo nuovi monomeri per poliuretani in condizioni blande e buona produttività. Capitolo-3. Facile Sintesi di nuovi 1-Ferrocenilmethilgliceroli e suoi derivati come agenti antifungini in assenza di solventi. Per la sintesi di derivati dei ferrocenilgliceroli (in principio utili come composti bioattivi) è stato studiato un metodo diretto e green consistente nella condensazione di ferrocenilalcanoli con glicerolo o suoi derivati in condizioni blande (20-90°C) con o senza co-solvente e/o catalizzatori. L’indagine ha riguardato la catalisi omogenea con acidi di Brönsted, ma una parte del lavoro è stato effettuata in collaborazione con l'Università di Pune (India), utilizzando come un catalizzatore eterogeneo ad acidità di Lewis il nitruro di alluminio (AIN/Al) nanometrico. Nella condensazione dei ferrocenilalcanoli con glicerolo o substrati 1,2 diolici si è poi studiato il ruolo della CO2 come promotore acido rivelatosi efficace ma non generale. I nuovi eteri ferrocenici preparati sono stati testati in vitro per la loro attività antifungina nei confronti di 3 diversi funghi, Fusarium spp., Botrytis cinerea, Penicillium spp. Gli esperimenti sono stati eseguiti per trattamento superficiale e inclusione delle culture di crescita, e hanno mostrato significativa attività antifungina, notevole per la semplicità dei substrati e la bassa tossicità. Nella direzione degli indolilmetani lo studio ha riguardato principalmente l’attività catalitica della nuova specie AlN/Al nella condensazione di composti carbonilici con indoli per dare i corrispondenti bis(indolil)metani, composti noti per essere biologicamente attivi. Oltre alla completa caratterizzazione di tale catalizzatore si è potuto dimostrare la stabilità e la riciclabilità (con turnover superiore a 100 cicli).Thesis title “Valorization of glycerol from biodiesel waste to high value chemicals” Suresh Udhavrao Shisodia, Tutor: Prof. Attilio Citterio. The present thesis will focus on the use and potentiality of glycerol (even crude) and ethyl lactate as C-3 chemical platforms obtained from biomass, to generate new green products, polymers, and bioactive compounds, under as much as possible green conditions. In the 21st century major issues are the generation of energy, sustainable chemicals & materials for industry, by less consumption of energy & reduce pollution by using biomass instead of fossil fuels. Glycerol has emerged as relevant renewable resource, spurred by the growing of the biodiesel production. It has more than 3000 different actual industrial uses but still surplus of glycerol needs to be valorized. Ethyl lactate emerged as important chemical commodity as environmentally benign solvent and reagent, which is obtained by esterification of lactic acid with ethanol, lactic acid is obtained from both bacteria and animal cells in an anaerobic respiration method. In this thesis work ethyl lactate was investigated mainly as green solvent for oxidations with hydrogen peroxide of organic compounds, identifying the eco-friendly peracids-like nature of this system. On the contrary, glycerol studies were addressed to control the chemo- and regio-selectivity of O and N nucleophilic substitutions to C-O bonds through activation of carbonate substituents, or electrophilic substitution to O-H bonds. In particular, the aim was to investigate the factors affecting the unexplored area of regio-selective poly-condensation of glycerol derivatives by using cascade and solvent free reactions by green methods, to produce stereo-ordered oligomers, polyglycerol ethers or urethanes and other functional products. In this area a further target was to synthesize simple derivatives by incorporate ferrocenyl or indolyl units to test the antifungal activity of the resulting products and identify the role of homo- & hetero- geneous catalysis in electrophilic substitution or alkylation reaction by stabilized cations (i.e. ferrocenylmethyl and hydroxyalkyl). The specific topics investigated can be summarized as follows (based on the thesis chapters): Chapter-1. Synthesis, purification, reactivity of diglycerol dicarbonate (DGDC) and conversion to stereoselective oligomers and polymers. In this context the following aspects were studied and explored: a) Green synthesis of DGDC from impure diglycerol using carbonatation reaction by thermal or by microwave irradiation; b) Purification of d,l- and meso-DGDC by crystallization; c) Hydrolysis of pure d,l- and meso- DGDC to stereoordered α-diglycerols; d) Selective nucleophilic substitution reactions at terminal C-O bond of pure d,l- and meso- DGDC by N and O centred nucleophiles, e) Selective synthesis of stereo-ordered monomer and polymers from pure d,l- and meso-DGDC diastereoisomers. In all cases progress of reactions were controlled by using TLC, HPLC, GC-mass or capillary electrophoresis and the purified products were obtained by silica gel column chromatography and crystallization, and then characterized via 1H-/13C-NMR, IR, and LCMS. X-ray crystallographic study and SEM analysis were made where ever necessary. For the characterization of polymers, DSC & TGA analysis were applied. The same analytical techniques were applied also in the following explored areas. Chapter-2. Cascade synthesis of α-glycerolcarbamates. Polyhydroxyurethanes are compounds of great interest having a wide range of applications in pharmacology, agriculture, and chemical industry, their conventional synthesis is based on the use of toxic reagents like isocyanates, phosgene, nitro derivatives, etc. It is important to substitute these reagents with green reagents like CO2 or organic carbonates, but the drastic conditions generally used with these reagents prevented any selective transformations on poly-substituted derivatives. In order to solve the problem we have developed a new efficient synthetic route for the preparation of difunctional and polyfunctional molecules from C-3 inherent natural polyol monomer glycerol and green alkyl carbonate. α-glycerolcarbamates were selectively synthesized by single-step three components system (glycerol, dialkyl carbonates, and aliphatic amines or polyamines). Factors affecting the selectivity at terminal to internal carbamate isomers were investigated and the key role of the intermediate in-situ formed linear carbonate ester of glycerol for selective substitution at the terminal position was ascertained. Inhibition of further substitution by the carbamate product was also observed, facilitating the selective mono-functionalization of substrate. By this approach polyurethanes can be obtained under mild conditions and good productivity by using di- or poly-amines. Chapter-3. Easy Solvent Free Synthesis of Novel 1-Ferrocenylmethylglycerols and its derivatives as antifungal agents. For the synthesis of ferrocenylglycerol derivatives (in principle useful as bioactive compounds) a direct, green method was studied consisting in condensing ferrocenylalkanols with glycerol or its derivatives under mild conditions (20-90°C) without or in the presence of co-solvent and/or catalyst. Homogeneous Brönsted acid catalysis was mainly investigated but some work was carried out, in collaboration with the Pune University (India), with the heterogeneous Lewis acid catalyst aluminum nitride (AlN/Al). The role of CO2 as promoter was investigated and proved effective, in condensation reactions of ferrocenylalkanols with glycerol or 1,2-diol substrates, but not in general. The novel ferrocenylglycerol derivatives were tested in vitro for their antifungal activity towards 3 different plant fungi, Fusarium spp., Botrytis cinerea, Penicillium spp. The experiments were performed by surface and inclusion treatment of the cultural growth mediums, and shown significant antifungal activity in surface treatment method. The novel AlN/Al catalyst was mainly investigated in the condensation of carbonyl compounds with indoles to afford the corresponding bis(indolyl)methanes, compounds known to be biologically active. The catalyst, characterized by SEM, Raman and particle size analysis, and is recyclable (retains its activity for 10 cycles) Chapter-4. Hydrogen peroxide/Ethyl lactate: A New Eco-Friendly Peracids-like System for the Oxidation of Organic Compounds. Oxidation of organic substrates by using H2O2 is a widely explored area, frequently applied on industrial scale. However H2O2 is relatively unreactive molecule and strong efforts have been devoted for selection and use of catalysts to accelerate or control the processes. Inorganic and metal catalysts were deeply investigated where as the use of organic catalyst was more scantly analyzed and applied (except for formation of alkyl or arylalkyl peroxides and peracids). However, for a “green oxidation” point of view the ideal system is the one which use environmentally-friendly oxidants together with recyclable catalysts in a nontoxic solvent. Thus, the use of organic solvents able to dissolve a wide variety of substrates and to activate H2O2 was explored as oxidant system, focusing on natural esters of α-hydroxy carboxylic acids. We found that ethyl lactate, an easily available, green and safe solvent, has the peculiarity to react rapidly with H2O2 to give an intermediate able to oxidize organic sulfides RSR', reduced organophosphorous substrates of general structure [PRx(OR)3-x with x = 0-2], to the corresponding oxygen addition products sulfoxides, phosphine oxides, phosphates, phosphinates and phosphonates, where as carbonyl compounds were converted to the ester in a Bayer-Villiger oxygen insertion reaction. The oxygenation of aryl methyl sulfides, follows an overall second-order kinetics, first order in H2O2 and sulfide and involve general acid catalysis. In p-substituted phenyl methyl sulfides the negative r value obtained in the correlation analysis of rate constants with s constants indicate that positive charge is generated on sulfur atom and the electrophilic oxygen of "perlactic acid" is responsible for the acceleration by electron withdrawing substituents. The fast decay of the peroxidic intermediate prevents the possibility to apply the system to less reactive substrates, i.e. olefins and electron withdrawing substituted aromatics.DIPARTIMENTO DI CHIMICA, MATERIALI E INGEGNERIA CHIMICA GIULIO NATTA25SERVI, STEFANOFARAVELLI, TIZIAN