Photoredox Catalysis and Nucleophilic Organometallic Reagents – Application in Organic Synthesis

The main purpose of my PhD was the combination of the principles of transition metal catalysis with photoredox catalysis. We focused our attention on the development of novel dual catalytic protocols for the functionalization of carbonyl compounds through the generation of transient nucleophilic organometallic species. Specifically, we focused on the development of new methodologies combining photoredox catalysis with titanium and nickel in low oxidation state. Firstly, a Barbier-type allylation of aromatic and aliphatic aldehydes –catalytic in titanium– in the presence of a blue photon-absorbing dye was developed. Parallelly, we were pleased to observe that the developed methodology could also be extended to the propargylation of aldehydes under analogous conditions. After an extensive re–optimization of all the reaction parameters, we developed an enantioselective and diastereoselective pinacol coupling of aromatic aldehydes promoted by non-toxic, cheap and easy to synthetize titanium complexes. The key feature, that allows the complete (dia)stereocontrol played by titanium, is the employment of a red-absorbing organic dye. The tailored (photo)redox properties of the red-absorbing organic dye [nPr–DMQA+][BF4–] promote the selective reduction of Ti(IV) to Ti(III). Moreover, even if the major contribution in dual photoredox and nickel catalysis is devoted to the realization of cross-coupling-type reactions, we wanted to evaluate different possible scenarios. Our focus was on the possibility of exploiting intermediates arising from the oxidative addition of nickel complexes as transient nucleophilic species. The first topic considered regarded the possibility to perform allylation of aldehydes by dual photoredox and nickel catalysis. In the first instance, a non–stereocontrolled version of the reaction was presented. Finally, after a long series of drastic modification of the reaction conditions, a highly enantioselective variant of the protocol was also reported. All the reported methodologies are supported by careful photophysical analysis and, in some cases, computational modelling.

Lipophilic nucleosides: studies toward self-assembled functional materials

Molecular self-assembly takes advantage of supramolecular non-covalent interactions (ionic, hydrophobic, van der Waals, hydrogen and coordination bonds) for the construction of organized and tunable systems. In this field, lipophilic guanosines can represent powerful building blocks thanks to their aggregation proprieties in organic solvents, which can be controlled by addition or removal of cations. For example, potassium ion can template the formation of piled G-quartets structures, while in its absence ribbon-like G aggregates are generated in solution. In this thesis we explored the possibility of using guanosines as scaffolds to direct the construction of ordered and self-assembled architectures, one of the main goals of bottom-up approach in nanotechnology. In Chapter III we will describe Langmuir-Blodgett films obtained from guanosines and other lipophilic nucleosides, revealing the “special” behavior of guanine in comparison with the other nucleobases. In Chapter IV we will report the synthesis of several thiophene-functionalized guanosines and the studies towards their possible use in organic electronics: the pre-programmed organization of terthiophene residues in ribbon aggregates could allow charge conduction through π-π stacked oligothiophene functionalities. The construction and the behavior of some simple electronic nanodevices based on these organized thiopehene-guanosine hybrids has been explored.

Innovative photoresponsive materials & supramolecular structures

This thesis focuses on two main topics: photoresponsive azobenzene-based polymers and supramolecular systems generated by the self-assembly of lipophilic guanosines. In the first chapters describe innovative photoresponsive devices and materials capable of performing multiple roles in the field of soft robotics and energy conversion. Chapter 2 describes a device obtained by coupling a photoresponsive liquid-crystalline network and a piezoelectric polymer to convert visible light into electricity. Chapter 3 deals with a material that can assume different shapes when triggered by three different stimuli in different environments. Chapter 4 reports a highly performing artificial muscle that contracts when irradiated. The last two chapters report on supramolecular structures generated from functionalized guanosines dissolved in organic solvents. Chapter 6 illustrates the self-assembly into G-quadruplexes of 8- and 5’-functionalized guanosines in the absence of templating ions. Chapter 7 describes the supramolecular structure generated by the assembly of a lipophilic guanosine in the presence of silver cations. Chapter 6 is reproduced from an already published paper, while the other chapters are going to be submitted to different journals in a couple of months.

Use of solvents and environmental friendly materials for applications in Green Chemistry

The present Thesis studies three alternative solvent groups as sustainable replacement of traditional organic solvents. Some aspects of fluorinated solvents, supercritical fluids and ionic liquids, have been analysed with a critical approach and their effective “greenness” has been evaluated from the points of view of the synthesis, the properties and the applications. In particular, the attention has been put on the environmental and human health issues, evaluating the eco-toxicity, the toxicity and the persistence, to underline that applicability and sustainability are subjects with equal importance. The “green” features of fluorous solvents and supercritical fluids are almost well-established; in particular supercritical carbon dioxide (scCO2) is probably the “greenest” solvent among the alternative solvent systems developed in the last years, enabling to combine numerous advantages both from the point of view of industrial/technological applications and eco-compatibility. In the Thesis the analysis of these two classes of alternative solvents has been mainly focused on their applicability, rather than the evaluation of their environmental impact. Specifically they have been evaluated as alternative media for non-aqueous biocatalysis. For this purpose, the hydrophobic ion pairing (HIP), which allows solubilising enzymes in apolar solvents by an ion pairing between the protein and a surfactant, has been investigated as effective enzymatic derivatisation technique to improve the catalytic activity under homogeneous conditions in non conventional media. The results showed that the complex enzyme-surfactant was much more active both in fluorous solvents and in supercritical carbon dioxide than the native form of the enzyme. Ionic liquids, especially imidazolium salts, have been proposed some years ago as “fully green” alternative solvents; however this epithet does not take into account several “brown” aspects such as their synthesis from petro-chemical starting materials, their considerable eco-toxicity, toxicity and resistance to biodegradation, and the difficulty of clearly outline applications in which ionic liquids are really more advantageous than traditional solvents. For all of these reasons in this Thesis a critical analysis of ionic liquids has been focused on three main topics: i) alternative synthesis by introducing structural moieties which could reduce the toxicity of the most known liquid salts, and by using starting materials from renewable resources; ii) on the evaluation of their environmental impact through eco-toxicological tests (Daphnia magna and Vibrio fischeri acute toxicity tests, and algal growth inhibition), toxicity tests (MTT test, AChE inhibition and LDH release tests) and fate and rate of aerobic biodegradation in soil and water; iii) and on the demonstration of their effectiveness as reaction media in organo-catalysis and as extractive solvents in the recovery of vegetable oil from terrestrial and aquatic biomass. The results about eco-toxicity tests with Daphnia magna, Vibrio fischeri and algae, and toxicity assay using cultured cell lines, clearly indicate that the difference in toxicity between alkyl and oxygenated cations relies in differences of polarity, according to the general trend of decreasing toxicity by decreasing the lipophilicity. Independently by the biological approach in fact, all the results are in agreement, showing a lower toxicity for compounds with oxygenated lateral chains than for those having purely alkyl lateral chains. These findings indicate that an appropriate choice of cation and anion structures is important not only to design the IL with improved and suitable chemico-physical properties but also to obtain safer and eco-friendly ILs. Moreover there is a clear indication that the composition of the abiotic environment has to be taken into account when the toxicity of ILs in various biological test systems is analysed, because, for example, the data reported in the Thesis indicate a significant influence of salinity variations on algal toxicity. Aerobic biodegradation of four imidazolium ionic liquids, two alkylated and two oxygenated, in soil was evaluated for the first time. Alkyl ionic liquids were shown to be biodegradable over the 6 months test period, and in contrast no significant mineralisation was observed with oxygenated derivatives. A different result was observed in the aerobic biodegradation of alkylated and oxygenated pyridinium ionic liquids in water because all the ionic liquids were almost completely degraded after 10 days, independently by the number of oxygen in the lateral chain of the cation. The synthesis of new ionic liquids by using renewable feedstock as starting materials, has been developed through the synthesis of furan-based ion pairs from furfural. The new ammonium salts were synthesised in very good yields, good purity of the products and wide versatility, combining low melting points with high decomposition temperatures and reduced viscosities. Regarding the possible applications as surfactants and biocides, furan-based salts could be a valuable alternative to benzyltributylammonium salts and benzalkonium chloride that are produced from non-renewable resources. A new procedure for the allylation of ketones and aldehydes with tetraallyltin in ionic liquids was developed. The reaction afforded high yields both in sulfonate-containing ILs and in ILs without sulfonate upon addition of a small amount of sulfonic acid. The checked reaction resulted in peculiar chemoselectivity favouring aliphatic substrates towards aromatic ketones and good stereoselectivity in the allylation of levoglucosenone. Finally ILs-based systems could be easily and successfully recycled, making the described procedure environmentally benign. The potential role of switchable polarity solvents as a green technology for the extraction of vegetable oil from terrestrial and aquatic biomass has been investigated. The extraction efficiency of terrestrial biomass rich in triacylglycerols, as soy bean flakes and sunflower seeds, was comparable to those of traditional organic solvents, being the yield of vegetable oils recovery very similar. Switchable polarity solvents as been also exploited for the first time in the extraction of hydrocarbons from the microalga Botryococcus braunii, demonstrating the efficiency of the process for the extraction of both dried microalgal biomass and directly of the aqueous growth medium. The switchable polarity solvents exhibited better extraction efficiency than conventional solvents, both with dried and liquid samples. This is an important issue considering that the harvest and the dewatering of algal biomass have a large impact on overall costs and energy balance.

Acqua: solvente elettivo in Organocatalisi e Biocatalisi

Water is a safe, harmless, and environmentally benign solvent. From an eco-sustainable chemistry perspective, the use of water instead of organic solvent is preferred to decrease environmental contamination. Moreover, water has unique physical and chemical properties, such as high dielectric constant and high cohesive energy density compared to most organic solvents. The different interactions between water and substrates, make water an interesting candidate as a solvent or co-solvent from an industrial and laboratory perspective. In this regard, organic reactions in aqueous media are of current interest. In addition, from practical and synthetic standpoints, a great advantage of using water is immediately evident, since it does not require any preliminary drying process. This thesis was found on this aspect of chemical research, with particular attention to the mechanisms which control organo and bio-catalysis outcome. The first part of the study was focused on the aldol reaction. In particular, for the first time it has been analyzed for the first time the stereoselectivity of the condensation reaction between 3-pyridincarbaldehyde and the cyclohexanone, catalyzed by morpholine and 4-tertbutyldimethylsiloxyproline, using water as sole solvent. This interest has resulted in countless works appeared in the literature concerning the use of proline derivatives as effective catalysts in organic aqueous environment. These studies showed good enantio and diastereoselectivities but they did not present an in depth study of the reaction mechanism. The analysis of the products diastereomeric ratios through the Eyring equation allowed to compare the activation parameters (ΔΔH≠ and ΔΔS≠) of the diastereomeric reaction paths, and to compare the different type of catalysis. While morpholine showed constant diasteromeric ratio at all temperatures, the O(TBS)-L-proline, showed a non-linear Eyring diagram, with two linear trends and the presence of an inversion temperature (Tinv) at 53 ° C, which denotes the presence of solvation effects by water. A pH-dependent study allowed to identify two different reaction mechanisms, and in the case of O(TBS)-L-proline, to ensure the formation of an enaminic species, as a keyelement in the stereoselective process. Moreover, it has been studied the possibility of using the 6- aminopenicillanic acid (6-APA) as amino acid-type catalyst for aldol condensation between cyclohexanone and aromatic aldehydes. A detailed analysis of the catalyst regarding its behavior in different organic solvents and pH, allowed to prove its potential as a candidate for green catalysis. Best results were obtained in neat conditions, where 6-APA proved to be an effective catalyst in terms of yields. The catalyst performance in terms of enantio- and diastereo-selectivity, was impaired by the competition between two different catalytic mechanisms: one via imine-enamine mechanism and one via a Bronsted-acid catalysis. The last part of the thesis was dedicated to the enzymatic catalysis, with particular attention to the use of an enzyme belonging to the class of alcohol dehydrogenase, the Horse Liver Alcohol Dehydrogenase (HLADH) which was selected and used in the enantioselective reduction of aldehydes to enantiopure arylpropylic alcohols. This enzyme has showed an excellent responsiveness to this type of aldehydes and a good tolerance toward organic solvents. Moreover, the fast keto-enolic equilibrium of this class of aldehydes that induce the stereocentre racemization, allows the dynamic-kinetic resolution (DKR) to give the enantiopure alcohol. By analyzing the different reaction parameters, especially the pH and the amount of enzyme, and adding a small percentage of organic solvent, it was possible to control all the parameters involved in the reaction. The excellent enatioselectivity of HLADH along with the DKR of arylpropionic aldehydes, allowed to obtain the corresponding alcohols in quantitative yields and with an optical purity ranging from 64% to >99%.

In situ real-time investigation of Organic Ultra-Thin-Film transistors: growth, electrical properties and biosensing applications

Organic electronics has grown enormously during the last decades driven by the encouraging results and the potentiality of these materials for allowing innovative applications, such as flexible-large-area displays, low-cost printable circuits, plastic solar cells and lab-on-a-chip devices. Moreover, their possible field of applications reaches from medicine, biotechnology, process control and environmental monitoring to defense and security requirements. However, a large number of questions regarding the mechanism of device operation remain unanswered. Along the most significant is the charge carrier transport in organic semiconductors, which is not yet well understood. Other example is the correlation between the morphology and the electrical response. Even if it is recognized that growth mode plays a crucial role into the performance of devices, it has not been exhaustively investigated. The main goal of this thesis was the finding of a correlation between growth modes, electrical properties and morphology in organic thin-film transistors (OTFTs). In order to study the thickness dependence of electrical performance in organic ultra-thin-film transistors, we have designed and developed a home-built experimental setup for performing real-time electrical monitoring and post-growth in situ electrical characterization techniques. We have grown pentacene TFTs under high vacuum conditions, varying systematically the deposition rate at a fixed room temperature. The drain source current IDS and the gate source current IGS were monitored in real-time; while a complete post-growth in situ electrical characterization was carried out. At the end, an ex situ morphological investigation was performed by using the atomic force microscope (AFM). In this work, we present the correlation for pentacene TFTs between growth conditions, Debye length and morphology (through the correlation length parameter). We have demonstrated that there is a layered charge carriers distribution, which is strongly dependent of the growth mode (i.e. rate deposition for a fixed temperature), leading to a variation of the conduction channel from 2 to 7 monolayers (MLs). We conciliate earlier reported results that were apparently contradictory. Our results made evident the necessity of reconsidering the concept of Debye length in a layered low-dimensional device. Additionally, we introduce by the first time a breakthrough technique. This technique makes evident the percolation of the first MLs on pentacene TFTs by monitoring the IGS in real-time, correlating morphological phenomena with the device electrical response. The present thesis is organized in the following five chapters. Chapter 1 makes an introduction to the organic electronics, illustrating the operation principle of TFTs. Chapter 2 presents the organic growth from theoretical and experimental points of view. The second part of this chapter presents the electrical characterization of OTFTs and the typical performance of pentacene devices is shown. In addition, we introduce a correcting technique for the reconstruction of measurements hampered by leakage current. In chapter 3, we describe in details the design and operation of our innovative home-built experimental setup for performing real-time and in situ electrical measurements. Some preliminary results and the breakthrough technique for correlating morphological and electrical changes are presented. Chapter 4 meets the most important results obtained in real-time and in situ conditions, which correlate growth conditions, electrical properties and morphology of pentacene TFTs. In chapter 5 we describe applicative experiments where the electrical performance of pentacene TFTs has been investigated in ambient conditions, in contact to water or aqueous solutions and, finally, in the detection of DNA concentration as label-free sensor, within the biosensing framework.

Social aspects of organic agriculture and other multifunctional benefits - Successful EU models compared with possibilities for organic developments in Croatia

Main objective of the dissertation is to illustrate how social and educational aspects (in close interaction with other multifunctional aspects in organic agriculture) which are developed on different multifunctional organic farms in Italy and Netherlands, as well as established agricultural policy frameworks in these countries, can be compared with the situation in Croatian organics and can contribute to further developent of organic issues in the Repubic of Croatia. So, through different chapters, the dissertation describes the performance of organic agriculture sectors in Italy, Netherlands and Croatia within the national agricultural policy frameworks, it analyzes the role of national institutions and policy in Croatia in connection with Croatia's status of candidate country for enterance into EU and harmonization of legislation with the CAP, as well as analyzes what is the role of national authorities, universities, research centres, but also of private initiatives, NGOs and cooperatives in organic agriculture in Netherlands, Italy and Croatia. Its main part describes how social and educational aspects are interacting with other multifunctional aspects in organic agriculture and analyzes the benefits and contribution of multifunctional activites performed on organic farms to education, healthy nourishment, environment protection and health care. It also assess the strengths and weaknesses of organic agriculture in all researched countries. The dissertation concludes with development opportunities for multifunctional organic agriculture in Croatia, as well as giving perspectives and recommendations for different approaches on the basis of experiences learned from successful EU models accompanied with some personal ideas and proposals.

Spectroscopic studies on Cyclodextrin and Metal Organic Framework based potential nanovectors for delivery of Anticancer and Antiviral drugs

The aim of this work is to contribute to the development of new multifunctional nanocarriers for improved encapsulation and delivery of anticancer and antiviral drugs. The work focused on water soluble and biocompatible oligosaccharides, the cyclodextrins (CyDs), and a new family of nanostructured, biodegradable carrier materials made of porous metal-organic frameworks (nanoMOFs). The drugs of choice were the anticancer doxorubicin (DOX), azidothymidine (AZT) and its phosphate derivatives and artemisinin (ART). DOX possesses a pharmacological drawback due to its self-aggregation tendency in water. The non covalent binding of DOX to a series of CyD derivatives, such as g-CyD, an epichlorohydrin crosslinked b-CyD polymer (pb-CyD) and a citric acid crosslinked g-CyD polymer (pg-CyD) was studied by UV visible absorption, circular dichroism and fluorescence. Multivariate global analysis of multiwavelength data from spectroscopic titrations allowed identification and characterization of the stable complexes. pg-CyD proved to be the best carrier showing both high association constants and ability to monomerize DOX. AZT is an important antiretroviral drug. The active form is AZT-triphosphate (AZT-TP), formed in metabolic paths of low efficiency. Direct administration of AZT-TP is limited by its poor stability in biological media. So the development of suitable carriers is highly important. In this context we studied the binding of some phosphorilated derivatives to nanoMOFs by spectroscopic methods. The results obtained with iron(III)-trimesate nanoMOFs allowed to prove that the binding of these drugs mainly occurs by strong iono-covalent bonds to iron(III) centers. On the basis of these and other results obtained in partner laboratories, it was possible to propose this highly versatile and “green” carrier system for delivery of phosphorylated nucleoside analogues. The interaction of DOX with nanoMOFs was also studied. Finally the binding of the antimalarial drug, artemisinin (ART) with two cyclodextrin-based carriers,the pb-CyD and a light responsive bis(b-CyD) host, was also studied.

Novel two photon absorbers: evaluation of photophysical properties in view of biomedical applications

This thesis was focused on the investigation of the linear optical properties of novel two photon absorbers for biomedical applications. Substituted imidazole and imidazopyridine derivatives, and organic dendrimers were studied as potential fluorophores for two photon bioimaging. The results obtained showed superior luminescence properties for sulphonamido imidazole derivatives compared to other substituted imidazoles. Imidazo[1,2-a]pyridines exhibited an important dependence on the substitution pattern of their luminescence properties. Substitution at imidazole ring led to a higher fluorescence yield than the substitution at the pyridine one. Bis-imidazo[1,2-a]pyridines of Donor-Acceptor-Donor type were examined. Bis-imidazo[1,2-a]pyridines dimerized at C3 position had better luminescence properties than those dimerized at C5, displaying high emission yields and important 2PA cross sections. Phosphazene-based dendrimers with fluorene branches and cationic charges on the periphery were also examined. Due to aggregation phenomena in polar solvents, the dendrimers registered a significant loss of luminescence with respect to fluorene chromophore model. An improved design of more rigid chromophores yields enhanced luminescence properties which, connected to large 2PA cross-sections, make this compounds valuable as fluorophores in bioimaging. The photophysical study of several ketocoumarine initiators, designed for the fabrication of small dimension prostheses by two photon polymerization (2PP) was carried out. The compounds showed low emission yields, indicative of a high population of the triplet excited state, which is the active state in producing the reactive species. Their efficiency in 2PP was proved by fabrication of microstructures and their biocompatibility was tested in the collaborator’s laboratory. In the frame of the 2PA photorelease of drugs, three fluorene-based dyads have been investigated. They were designed to release the gamma-aminobutyric acid via two photon induced electron transfer. The experimental data in polar solvents showed a fast electron transfer followed by an almost equally fast back electron transfer process, which indicate a poor optimization of the system.

In-situ and real time scanning probe microscopy of organic ultra thin films

In recent decades, Organic Thin Film Transistors (OTFTs) have attracted lots of interest due to their low cost, large area and flexible properties which have brought them to be considered the building blocks of the future organic electronics. Experimentally, devices based on the same organic material deposited in different ways, i.e. by varying the deposition rate of the molecules, show different electrical performance. As predicted theoretically, this is due to the speed and rate by which charge carriers can be transported by hopping in organic thin films, transport that depends on the molecular arrangement of the molecules. This strongly suggests a correlation between the morphology of the organic semiconductor and the performance of the OTFT and hence motivated us to carry out an in-situ real time SPM study of organic semiconductor growth as an almost unprecedent experiment with the aim to fully describe the morphological evolution of the ultra-thin film and find the relevant morphological parameters affecting the OTFT electrical response. For the case of 6T on silicon oxide, we have shown that the growth mechanism is 2D+3D, with a roughening transition at the third layer and a rapid roughening. Relevant morphological parameters have been extracted by the AFM images. We also developed an original mathematical model to estimate theoretically and more accurately than before, the capacitance of an EFM tip in front of a metallic substrate. Finally, we obtained Ultra High Vacuum (UHV) AFM images of 6T at lying molecules layer both on silicon oxide and on top of 6T islands. Moreover, we performed ex-situ AFM imaging on a bilayer film composed of pentacene (a p-type semiconductor) and C60 (an n-type semiconductor).

Sewage sludge as organic fertilizer in agriculture. A study of physico-chemical properties, agronomic efficiency and environmental safety, with a specific focus on tannery sludge

In recent decades, the use of organic fertilizers has gained increasing interest mainly for two reasons: their ability to improve soil fertility and the need to find a sustainable alternative to mineral and synthetic fertilizers. In this context, sewage sludge is a useful organic matrix that can be successfully used in agriculture, due to its chemical composition rich in organic matter, nitrogen, phosphorus and other micronutrients necessary for plant growth. This work investigated three indispensable aspects (i.e., physico-chemical properties, agronomic efficiency and environmental safety) of sewage sludge application as organic fertilizer, emphasizing the role of tannery sludge. In a comparison study with municipal sewage sludge, results showed that the targeted analyses applied (total carbon and nitrogen content, isotope ratio of carbon and nitrogen, infrared spectroscopy and thermal analysis) were able to discriminate tannery sludge from municipal ones, highlighting differences in composition due to the origin of the wastewater and the treatment processes used in the plants. Regarding agronomic efficiency, N bioavailability was tested in a selection of organic fertilizers, including tannery sludge and tannery sludge-based fertilizers. Specifically, the hot-water extractable N has proven to be a good chemical indicator, providing a rapid and reliable indication of N bioavailability in soil. Finally, the behavior of oxybenzone (an emerging organic contaminant detected in sewage sludge) in soils with different physico-chemical properties was studied. Through adsorption and desorption experiments, it was found that the mobility of oxybenzone is reduced in soils rich in organic matter. Furthermore, through spectroscopic methods (e.g., infrared spectroscopy and surface-enhanced Raman spectroscopy) the mechanisms of oxybenzone-humic acids interaction were studied, finding that H-bonds and π-π stacking were predominantly present.

Design and characterization of polymorphs and co-crystals of organic molecular semiconductors

In the last decades, organic semiconductors have attracted attention due to their possible employment in solution-processed optoelectronic and electronic devices. One of the advantages of solution processing is the possibility to process into flexible substrates at low cost. Organic molecular materials tend to form polymorphs, which can exhibit very different properties. In most cases, the control of the crystal structure is decisive to maximize the performance of the final device. Although organic electronics have progressed a lot, n-type organic semiconductors still lag behind p-type, presenting challenges such as air instability and poor solubility. NDI derivatives are promising candidates for applications in organic electronics due to their characteristics. Recently, the structure-properties relationship and the polymorphism of these molecules have gained attention. In the first part of this thesis, NDI-C6 thermal behavior was extensively explored which revealed two different behaviors depending on the annealing process. This study allowed to define the stability ranking of the NDI-C6 bulk forms and to determine the crystal structure of Form γ at 54°C. Additionally, the polymorphic and thermal behavior of thin films of NDI-C6 was also explored. It was possible to isolate pure Form α, Form β, Form γ and a new metastable Form ε. It was also possible to determine the stability ranking of the phases in thin films. OFETs were fabricated having different polymorphs as active layer, unfortunately the performance was not ideal. During the second part of this thesis, core-chlorinated NDIs with fluoroalkyl chains were studied. Initially, the focus was on the polymorphism of CF3-NDI that revealed a solvate form with a very interesting molecular arrangement suggesting the possibility to form charge transfer co-crystals. In the last part of the thesis, the synthesis and characterization of CT co-crystal with different NDI derivatives, and acceptor and as donor BTBT and ditBu-BTBT were explored.

TIDES unveiled: pioneering green peptides synthesis and oligonucleotides innovations in science

My PhD research focused on the development of environmentally sustainable methods for peptide synthesis. The traditional and toxic solvents and bases used in solid-phase peptide synthesis (SPPS) were replaced with eco-friendly alternatives to reduce the environmental impact. In particular, N-octylpyrrolidone was found to be an effective green solvent in combination with dimethyl carbonate, resulting in a 63-66% reduction in process mass intensity (PMI). In addition, a green base, DEAPA, was identified for Fmoc removal, which showed comparable results to piperidine, while being less regulated and toxic, and able to better control aspartimide-related side reactions. The study extended beyond SPPS to explore liquid-phase peptide synthesis (LPPS) and solution-phase peptide synthesis (SolPPS) using propylphosphonic anhydride (T3P®) as a coupling reagent. The developed green SolPPS using Cbz amino acids achieved exceptional efficiency, minimal racemisation and a PMI of 30 to introduce a single amino acid in the iterative process. This PMI value is the lowest ever reported for an oligopeptide synthesis protocol. This technique was extended to N-Boc amino acids in DCM, requiring aqueous workups and achieving 95% purity of Leu-Enkephalin. Finally, T3P® was found to be suitable for LPPS. An anchor, mimicking a resin, was used to allow precipitation or solubilisation of the growing anchored-peptide, depending on the polarity of the solvent used. Anisole and DCM resulted in a pentapeptide purity of over 95%. While at Oxford University, I synthesized a cleavable fragment that is sensitive to cathepsin B (CatB) and incorporated it into a cyclic antisense oligonucleotide (ASO) targeting the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). ASO demonstrated good stability in a simulated in vivo environment using human serum and high affinity with complementary RNA. The Cyclic-ASO was opened by CatB in optimal conditions. Experiments highlight therapeutic potential and a novel method for controlling cyclic oligonucleotide activity, potentially enhancing cellular uptake.