Unconventional Catalysis in Organic Chemistry: a Computational Mechanistic Study

Catalysis plays a vital role in modern synthetic chemistry. However, even if conventional catalysis (organo-catalysis, metal-catalysis and enzyme-catalysis) has provided outstanding results, various unconventional ways to make chemical reactions more effective appear now very promising. Computational methods can be of great help to reach a deeper comprehension of these chemical processes. The methodologies employed in this thesis are Quantum-Mechanical (QM), Molecular Mechanics (MM) and hybrid Quantum-Mechanical/Molecular Mechanics (QM/MM) methods. In this abstract the results are briefly summarised. The first unconventional catalysis investigated consists in the application of Oriented External Electric Fields (OEEFs) to SN2 and 4e-electrocyclic reactions. SN2 reactions with back-side mechanism can be catalysed or inhibited by the presence of an OEEF. Moreover, OEEFs can inhibit back-side mechanism (Walden inversion of configuration) and promote the naturally unfavoured front-side mechanism (retention of configuration). Electrocyclic ring opening reaction of 3-substituted cyclobutene molecules can occur with inward or outward mechanisms depending on the nature of substituent groups on the cyclobutene structure (torquoselectivity principle). OEEFs can catalyse the naturally favoured pathway or circumvent the torquoselectivity principle leading to different stereoisomers. The second case study is based on Carbon Nanotubes (CNTs) working as nano-reactors: the reaction of ethyl chloride with chloride anion inside CNTs was investigated. In addition to the SN2 mechanism, syn and anti-E2 reactions are possible. These reactions inside CNTs of different radii were examined with hybrid QM/MM methods, finding that these processes can be both catalysed and inhibited by the CNT diameter. The results suggest that electrostatic effects govern the activation energy variations inside CNTs. Finally, a new biochemical approach, based on the use of DNA catalyst was investigated at QM level. Deoxyribozyme 9DB1 catalyses the RNA ligation allowing the regioselective formation of the 3'-5' bond, following an addition-elimination two-step mechanism.

Novel developments of atropisomeric organic molecules. Design of atropisomeric drugs, fluorescent compounds and investigation of reaction mechanisms.

In recent years, the study of restricted rotation bonds in organic compounds has aroused increasing interest. The reason is that this characteristic can lead to obtaining new properties in organic compounds. In this research thesis, an intense investigation was carried out using DFT calculations and experimental evaluation of the barriers to rotational energies, in order to discover new properties deriving from the restricted rotation bonds. Research has been developed in various fields of organic chemistry, ranging from drugs (the atropisomeric atorvastatin in Chapter 3) to luminescent compounds (aryls amino borane in Chapter 4). Furthermore, an organocatalytic central to axial conversion mechanism was investigated through DFT calculations, finding out interesting outcomes (Chapter 5). Finally, a project in collaboration with Dr. Farran and Prof. Vanthuyne of the Aix-Marseille University was done to investigate the interactions in transition states of rotational barriers.

Organocatalytic asymmetric mannich-type reactions: an easy approach to optically active amine derivatives

The topics I came across during the period I spent as a Ph.D. student are mainly two. The first concerns new organocatalytic protocols for Mannich-type reactions mediated by Cinchona alkaloids derivatives (Scheme I, left); the second topic, instead, regards the study of a new approach towards the enantioselective total synthesis of Aspirochlorine, a potent gliotoxin that recent studies indicate as a highly selective and active agent against fungi (Scheme I, right). At the beginning of 2005 I had the chance to join the group of Prof. Alfredo Ricci at the Department of Organic Chemistry of the University of Bologna, starting my PhD studies. During the first period I started to study a new homogeneous organocatalytic aza-Henry reaction by means of Cinchona alkaloid derivatives as chiral base catalysts with good results. Soon after we introduced a new protocol which allowed the in situ synthesis of N-carbamoyl imines, scarcely stable, moisture sensitive compounds. For this purpose we used α-amido sulfones, bench stable white crystalline solids, as imine precursors (Scheme II). In particular we were able to obtain the aza-Henry adducts, by using chiral phase transfer catalysis, with a broad range of substituents as R-group and excellent results, unprecedented for Mannich-type transformations (Scheme II). With the optimised protocol in hand we have extended the methodology to the other Mannich-type reactions. We applied the new method to the Mannich, Strecker and Pudovik (hydrophosphonylation of imines) reactions with very good results in terms of enantioselections and yields, broadening the usefulness of this novel protocol. The Mannich reaction was certainly the most extensively studied work in this thesis (Scheme III). Initially we developed the reaction with α-amido sulfones as imine precursors and non-commercially available malonates with excellent results in terms of yields and enantioselections.3 In this particular case we recorded 1 mol% of catalyst loading, very low for organocatalytic processes. Then we thought to develop a new Mannich reaction by using simpler malonates, such as dimethyl malonate.4 With new optimised condition the reaction provided slightly lower enantioselections than the previous protocol, but the Mannich adducts were very versatile for the obtainment of β3-amino acids. Furthermore we performed the first addition of cyclic β-ketoester to α-amido sulfones obtaining the corresponding products in good yield with high level of diastereomeric and enantiomeric excess (Scheme III). Further studies were done about the Strecker reaction mediated by Cinchona alkaloid phase-transfer quaternary ammonium salt derivatives, using acetone cyanohydrin, a relatively harmless cyanide source (Scheme IV). The reaction proceeded very well providing the corresponding α-amino nitriles in good yields and enantiomeric excesses. Finally, we developed two new complementary methodologies for the hydrophosphonylation of imines (Scheme V). As a result of the low stability of the products derived from aromatic imines, we performed the reactions in mild homogeneous basic condition by using quinine as a chiral base catalyst giving the α-aryl-α-amido phosphonic acid esters as products (Scheme V, top).6 On the other hand, we performed the addition of dialkyl phosphite to aliphatic imines by using chiral Cinchona alkaloid phase transfer quaternary ammonium salt derivatives using our methodology based on α-amido sulfones (Scheme V, bottom). The results were good for both procedures covering a broad range of α-amino phosphonic acid ester. During the second year Ph.D. studies, I spent six months in the group of Prof. Steven V. Ley, at the Department of Chemistry of the University of Cambridge, in United Kingdom. During this fruitful period I have been involved in a project concerning the enantioselective synthesis of Aspirochlorine. We provided a new route for the synthesis of a key intermediate, reducing the number of steps and increasing the overall yield. Then we introduced a new enantioselective spirocyclisation for the synthesis of a chiral building block for the completion of the synthesis (Scheme VI).

Campionamento e determinazione di sostanze rilevanti per la valutazione della capacità ossidante dell’atmosfera e studio del loro effetto sui materiali ceramici

Carbonyl compounds are very important volatil organic compounds receiving increasing attention due to their critical role in tropospheric organic chemistry and to their effects on human health. They are first photo-oxidation stage of almost all organic compounds and originators of free radicals (OH, O3...). Therfore, continuous determination of their atmospheric concentrations is essential. Currently, field measurements are very limited mainly because of the analytical challenges posed by trace concentrations and interferences arising from atmospheric co-pollutants. Additionally, hydroxyl radical (OH) plays a central role in atmospheric chemistry processes. The measurement of atmospheric OH concentrations is essential for the comprehension of atmospheric chemical and photochemical processes. In this context, objectives of this work were: To perform a continuous survey of atmospheric concentrations of carbonyl compounds on different sites around the area of Bologna. For this purpose, an automatic instrument for the continuous measurement (one hour of time resolution) was developed and used. Additionally, the development of a complete and original analytical method was realised. To develop an original OH generation system in order to evaluate the effect of OH and the reactivity of solid and/or liquid materials of interest. This included the validation of an analytical method for the quantification of OH concentrations generated. Effect of OH on ceramic materials and reactivity of snow surface samples, involved as sink of OH in atmospheric chemistry, were evaluated.

Nuovi processi catalitici per la sintesi di prodotti ad attività farmacologica

The transition metal-catalyzed allylic alkylation (Tsuji-Trost type reaction) is a powerful tool for C-C, C-N, and C-O bond formation, which has been widely applied to organic chemistry over the last decades. Typical substrates for this transformation are activated allylic compounds such as halides, esters, carbonates, carbamates, phosphates, and so on. However, use of these substrates is associated with the disadvantage of generating a stoichiometric amount of chemical waste. Furthermore, these starting materials have to be prepared in an extra step from the corresponding allylic alcohol. Thus, ideal substrates would be the allylic alcohols themselves, with water being the only byproduct in this case. However, the scarse propensity of the hydroxyl moiety to act as good leaving group has significantly limited their use so far. During the last decade significant efforts have been made in order to develop more atom-economical and environmentally-friendly allylic alkylation protocols by employing allylic alcohols directly. In this PhD dissertation two main projects addressing this topic are presented. “Project 1” deals with the development of new metal-catalyzed intramolecular Friedel-Crafts (FC) allylic alkylations of electron-rich (PAPER A), as well as challenging electron-poor arenes (PAPER B) with alcohols. In “Project 2”, gold(I)-catalyzed intramolecular and stereoselective allylic alkylation reactions are reported. In particular, a FC alkylation of indole-containing allylic alcohols is presented in PAPER C. While, an O-alkylation of aminol-containing allylic alcohols is reported in PAPER D. To the best of knowledge, these reports represent the first example of gold(I)-catalyzed stereoselective alkylations with alcohols.

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.

Bioconjugation and synthetic approach towards enantioenriched gem-difluoromethylene compounds through carbenium ions

Bioconjugation of peptides and asymmetric synthesis of gem-difluoromethylene compounds are areas of the modern organic chemistry for which mild and selective methods continue to be developed. This thesis reports new methodologies for these two areas based on the use of stabilized carbenium ions. The reaction that makes the bioconjugation of peptides possible takes place via the direct nucleophilic substitution of alcohols and is driven by the spontaneous formation of stabilized carbenium ions in water. By reacting with the thiol group of cysteine in very mild conditions and with a high selectivity, these carbenium ions allow the site-specific ligation of polypeptides containing cysteine and their covalent derivatization with functionalized probes. The ligation of the indole ring of tryptophan, an emerging target in bioconjugation, is also shown and takes place in the same conditions. The second area investigated is the challenging access to optically active gem-difluoromethylene compounds. We describe a methodology relying on the synthesis of enantioenriched 1,3-benzodithioles intermediates that are shown to be precursors of the corresponding gem-difluoromethylene analogues by oxidative desulfurization-fluorination. This synthesis takes advantage of the highly enantioselective organocatalytic α-alkylation of aldehydes with the benzodithiolylium ion and of the wide possibilities of synthetic transformations offered by the 1,3-benzodithiole group. This approach allows the asymmetric access to complex gem-difluoromethylene compounds through a late-stage fluorination step, thus avoiding the use of fluorinated building blocks.

Study of medicinal and food plants as a source of biologically active compounds.

In the last few decades, scientific evidence has pointed out the health-beneficial effects of phenolic compounds in foods, including a decrease in risk of developing degenerative and chronic diseases, known to be caused by oxidative stress. In this frame can be inserted research carried out during my PhD thesis, which concerns the phytochemical investigation of phenolic composition in sweet cherries (Prunus avium L.), apple fruits (Malus domestica L.) and quinoa seeds (Chenopodium quinoa Willd.). The first project was focused on the investigation of phytochemical profile and nutraceutical value of fruits of new sweet cherry cultivars. Their phenolic profile and antioxidant activity were investigated and compared with those of commonly commercialized cultivars. Their nutraceutical value was evaluated in terms of antioxidant/neuroprotective capacity in neuron-like SH-SY5Y cells, in order to investigate their ability to counteract the oxidative stress and/or neurodegeneration process The second project was focused on phytochemical analysis of phenolic compounds in apples of ancient cultivars with the aim of selecting the most diverse cultivars, that will then be assayed for their anti-carcinogenic and anti-proliferative activities against the hepato-biliary and pancreatic tumours. The third project was focused on the analysis of polyphenolic pattern of seeds of two quinoa varieties grown at different latitudes. Analysis of phenolic profile and in vitro antioxidant activity of seed extracts both in their free and soluble-conjugated forms, showed that the accumulation of some classes of flavonoids is strictly regulated by environmental factors, even though the overall antioxidant capacity does not differ in quinoa Regalona grown in Chile and Italy. During the internship period carried out at the Department of Organic Chemistry at Universidad Autónoma de Madrid (UAM), it was achieved the isolation of two pentacyclic triterpenoids, from an endemic Peruvian plant, Jatropha macrantha Müll. Arg., with bio-guided fractionation technique.

E-cadherin and Choline Kinase: two challenging drug discovery targets

The data presented in this thesis was generated using molecular biology, protein chemistry and X-ray crystallography techniques. However, while the methodologies employed are essentially the same, the research work presented here refers to two different proteins, which are part of different research projects in the laboratory. For this reason, the content of this thesis is divided in two independent parts, each provided with an introduction and a general overview of the research topic and state-ofthe- art, a materials and methods section discussing the techniques used and the protocols followed, and a section where the results are presented and discussed in detail. The first half of the thesis deals with the structural characterization of the complex between human E-cadherin and three different small molecule potential inhibitors identified via a fragment-based drug discovery (FBDD) screening campaign that was conducted using a library of commercially available small fluorinated chemical fragments. For this screening phase, we used 19F-NMR as readout. The NMR experiments were done by our collaborator Dr. Marina Veronesi at the D3 PharmaChemistry division of the Italian Institute of Technology (IIT) in Genova (Italy). Functional cell adhesion assays to validate the inhibitory effects of the fragments thus identified were carried out in collaboration with Prof. Frédéric André at the University of Marseille (France). The second half of the thesis describes the structural characterization of Plasmodium falciparum Choline Kinase (PfChoK), an important pharmaceutical target in the fight against malaria, as well as the biochemical characterization of a library of potential inhibitors of PfChoK. These inhibitors were synthetized in the group of Prof. Luisa Carlota López-Cara at the Department of Pharmaceutical and Organic Chemistry of the University of Granada (Spain) in the framework of an ongoing collaboration between the two groups.

New Gold(I) complexes: from ligand design to homogeneous catalysis

This PhD thesis summarize the work carried out during three years of PhD course. Several thematic concerning gold(I) chemistry are analysed by crossing data from different chemistry areas as: organic chemistry, organometallic chemistry, inorganic chemistry and computational chemistry. In particular, the thesis focuses its attention on the evaluation of secondary electronic interactions, subsisting between ligand and Au(I) metal centre in the catalyst, and their effects on catalytic activity. The interaction that has been taken in consideration is the Au…Ar π-interaction which is known to prevent the decomposition of catalyst, but exhaustive investigations of further effects has never been done so far. New libraries of carbene (ImPy) and biarylphosphine ligands have been designed and synthetized for the purpose and subsequently utilized for the synthesis of corresponding Au(I) complexes. Resulting catalysts are tested in various catalytic processes involving different intermediates and in combination with solid state information from SC-XRD revealed an unprecedented activation mode which is only explained by considering both electronic nature and strength of Au…Ar π-interaction. DFT calculation carried on catalysis intermediates are in agreement with experimental ones, giving robustness to the theory. Moreover, a new synthetic protocol for the lactonization of N-allenyl indole-2-carboxylic acids is presented. Reaction conditions are optimized with the newly synthetized ImPy-Au(I) catalysts and different substrates are also tested providing a quite broad reaction scope. Chiral ImPy ligands have also been developed for the asymmetric variant of the same reaction and encouraging enantiomeric excess are obtained.

New catalytic strategies for the manipulation of arenes

The aim of this Doctoral Thesis is the development of new catalytic synthetic methodologies in the context of the modern organic chemistry setting, with special focus on the use of cheap, sustainable catalytic materials. Specifically, during the course my PhD, I focused my research on two main distinct catalytic strategies, namely: the use of carbonaceous materials as catalysts (carbocatalysis) and nickel catalysis, also investigating a synergistic combination of the two. These methodologies were explored as means for the manipulation of (hetero)aromatic cores, representing ubiquitous, easily accessible and privileged scaffolds in medicinal or natural products chemistry. Both polar and radical reaction manifolds were engaged as complementary reactivities, capitalizing on metal- as well as organo-based activation modes. Particular attention has been devoted to addressing modern synthetic challenges or highly sought- after methodologies. Specifically, protocols for direct substitution of alcohols, dearomatization of arene nuclei, formation of C-S bonds, carbon dioxide fixation, C-C bond activation and fluoroalkylation were successfully achieved under carbo- or nickel catalyzed conditions.

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.

Synthesis and Physical-Chemical characterization of Metallic Nanoparticles

The stabilization of nanoparticles against their irreversible particle aggregation and oxidation reactions. is a requirement for further advancement in nanoparticle science and technology. For this reason the research aim on this topic focuses on the synthesis of various metal nanoparticles protected with monolayers containing different reactive head groups and functional tail groups. In this work cuprous bromide nanocrystals haave been synthetized with a diameter of about 20 nanometers according to a new sybthetic method adding dropwise ascorbic acid to a water solution of lithium bromide and cupric chloride under continuous stirring and nitrogen flux. Butane thiolate Cu protected nanoparticles have been synthetized according to three different syntesys methods. Their morphologies appear related to the physicochemical conditions during the synthesis and to the dispersing medium used to prepare the sample. Synthesis method II allows to obtain stable nanoparticles of 1-2 nm in size both isolated and forming clusters. Nanoparticle cluster formation was enhanced as water was used as dispersing medium probably due to the idrophobic nature of the butanethiolate layers coating the nanoparticle surface. Synthesis methods I and III lead to large unstable spherical nanoparticles with size ranging between 20 to 50 nm. These nanoparticles appeared in the TEM micrograph with the same morphology independently on the dispersing medium used in the sample preparation. The stability and dimensions of the copper nanoparticles appear inversely related. Using the same methods above described for the butanethiolate protected copper nanoparticles 4-methylbenzenethiol protected copper nanoparticles have been prepared. Diffractometric and spectroscopic data reveal that decomposition processes didn’t occur in both the 4-methylbenzenethiol copper protected nanoparticles precipitates from formic acid and from water in a period of time six month long. Se anticarcinogenic effects by multiple mechanisms have been extensively investigated and documented and Se is defined a genuine nutritional cancer-protecting element and a significant protective effect of Se against major forms of cancer. Furthermore phloroglucinol was found to possess cytoprotective effects against oxidative stress, thanks to reactive oxygen species (ROS) which are associated with cells and tissue damages and are the contributing factors for inflammation, aging, cancer, arteriosclerosis, hypertension and diabetes. The goal of our work has been to set up a new method to synthesize in mild conditions amorphous Se nanopaticles surface capped with phloroglucinol, which is used during synthesis as reducing agent to obtain stable Se nanoparticles in ethanol, performing the synergies offered by the specific anticarcinogenic properties of Se and the antioxiding ones of phloroalucinol. We have synthesized selenium nanoparticles protected by phenolic molecules chemically bonded to their surface. The phenol molecules coating the nanoparticles surfaces form low ordered arrays as can be seen from the wider shape of the absorptions in the FT-IR spectrum with respect to those appearing in that of crystalline phenol. On the other hand, metallic nanoparticles with unique optical properties, facile surface chemistry and appropriate size scale are generating much enthusiasm in nanomedicine. In fact Au nanoparticles has immense potential for both cancer diagnosis and therapy. Especially Au nanoparticles efficiently convert the strongly adsorbed light into localized heat, which can be exploited for the selective laser photothermal therapy of cancer. According to the about, metal nanoparticles-HA nanocrystals composites should have tremendous potential in novel methods for therapy of cancer. 11 mercaptoundecanoic surface protected Au4Ag1 nanoparticles adsorbed on nanometric apathyte crystals we have successfully prepared like an anticancer nanoparticles deliver system utilizing biomimetic hydroxyapatyte nanocrystals as deliver agents. Furthermore natural chrysotile, formed by densely packed bundles of multiwalled hollow nanotubes, is a mineral very suitable for nanowires preparation when their inner nanometer-sized cavity is filled with a proper material. Bundles of chrysotile nanotubes can then behave as host systems, where their large interchannel separation is actually expected to prevent the interaction between individual guest metallic nanoparticles and act as a confining barrier. Chrysotile nanotubes have been filled with molten metals such as Hg, Pb, Sn, semimetals, Bi, Te, Se, and with semiconductor materials such as InSb, CdSe, GaAs, and InP using both high-pressure techniques and metal-organic chemical vapor deposition. Under hydrothermal conditions chrysotile nanocrystals have been synthesized as a single phase and can be utilized as a very suitable for nanowires preparation filling their inner nanometer-sized cavity with metallic nanoparticles. In this research work we have synthesized and characterized Stoichiometric synthetic chrysotile nanotubes have been partially filled with bi and monometallic highly monodispersed nanoparticles with diameters ranging from 1,7 to 5,5 nm depending on the core composition (Au, Au4Ag1, Au1Ag4, Ag). In the case of 4 methylbenzenethiol protected silver nanoparticles, the filling was carried out by convection and capillarity effect at room temperature and pressure using a suitable organic solvent. We have obtained new interesting nanowires constituted of metallic nanoparticles filled in inorganic nanotubes with a inner cavity of 7 nm and an isolating wall with a thick ranging from 7 to 21 nm.