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Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disease with no cure to date. Therapeutic agents used to treat ALS are very limited, although combined therapies may offer a more effective treatment strategy. Herein, we have studied the potential of nanomedicine to prepare a single platform based on mesoporous silica nanoparticles (MSNs) for the treatment of an ALS animal model with a cocktail of agents such as leptin (neuroprotective) and pioglitazone (anti-inflammatory), which have already demonstrated promising therapeutic ability in other neurodegenerative diseases. Our goal is to study the potential of functionalized mesoporous materials as therapeutic agents against ALS using MSNs as nanocarriers for the proposed drug cocktail leptin/pioglitazone (bMSN-LEP-PIO/b). The nanostructured materials have been characterized by different techniques, which confirmed the incorporation of both agents in the nanosystem. Subsequently, the effect,iin vivo/i, of the proposed drug cocktail,bMSN-LEP-PIO/b, was used in the murine model of TDP-43 proteinopathy (TDP-43supA315T/supmice). Body weight loss was studied, and using the rotarod test, motor performance was assessed, observing a continuous reduction in body weight and motor coordination in TDP-43supA315T/supmice and wild-type (WT) mice. Nevertheless, the disease progression was slower and showed significant improvements in motor performance, indicating that TDP-43supA315T/supmice treated withbMSN-LEP-PIO/bseem to have less energy demand in the late stage of the symptoms of ALS. Collectively, these results seem to indicate the efficiency of the systemsiin vivo/iand the usefulness of their use in neurodegenerative models, including ALS.

Ultrareactive F-doped mesoporous TiO2 nanoparticles with potential environmental applications have been synthesized using green natural carboxylic acids.

Cancer is the leading cause of death in the developed world. In the last few decades, photodynamic therapy (PDT) has augmented the number of medical techniques to treat this disease in the clinics. As the pharmacological active species to kill cancer cells are only generated upon light irradiation, PDT is associated with an intrinsic first level of selectivity. However, since PDT agents also accumulate in the surrounding, healthy tissue and since it is practically very challenging to only expose the tumor site to light, some side effects can be observed. Consequently, there is a need for a selective drug delivery system, which would give a second level of selectivity. In this work, a dual tumor targeting approach is presented based on mesoporous silica nanoparticles, which act by the enhanced permeability and retention effect, and the conjugation to folic acid, which acts as a targeting moiety for folate receptor-overexpressed cancer cells. The conjugates were found to be nontoxic in noncancerous human normal lung fibroblast cells while showing a phototoxic effect upon irradiation at 480 or 540 nm in the low nanomolar range in folate receptor overexpressing cancerous human ovarian carcinoma cells, demonstrating their potential for cancer targeted treatment.

Since the pioneering work of Vallet-Regí’s group on the design and synthesis of mesoporous silica-based materials with therapeutic applications, during the last 15 years, the potential use of mesoporous silica nanostructured materials as drug delivery vehicles has been extensively explored. The versatility of these materials allows the design of a wide variety of platforms that can incorporate numerous agents of interest (fluorophores, proteins, drugs, etc.) in a single scaffold. However, the use of these systems loaded with metallodrugs as cytotoxic agents against different diseases and with distinct therapeutic targets has been studied to a much lesser extent. This review will focus on the work carried out in this field, highlighting both the pioneering and recent contributions of Spanish groups that have synthesized a wide variety of systems based on titanium, tin, ruthenium, copper and silver complexes supported onto nanostructured silica. In addition, this article will also discuss the importance of the structural features of the systems for evaluating and modulating their therapeutic properties. Finally, the most interesting results obtained in the study of the potential therapeutic application of these metallodrug-functionalized silica-based materials against cancer and bacteria will be described, paying special attention to preclinical trials in vivo.

Schiff base Cu(II), Co(II), Ni(II), Cr(III) and Fe(III) complexes have been synthesized via the reaction of the 2-amino-3-hydroxy-4-bromopyridine with 2-chloro-5-nitrobenzaldehyde and different transition metal salts. The complexes have been characterized by several methods. In addition, the prepared complexes were tested as precursors for the synthesis of their corresponding metal oxides nanoparticles by controlled aerobic thermal decomposition at 500 °C. The structure, composition, morphology and particle size of the prepared nanostructured metal oxides were characterized by FTIR, X-ray powder diffraction and by scanning and transmission electron microscopy. In addition, the corresponding materials have been tested as catalysts in the heterogeneous selective “solvent free” oxidation of benzyl alcohol giving high selectivities to benzaldehyde. In addition, the nanostructured metal oxides gave, in general, higher conversions than those of the starting Schiff base metal complexes. Finally, the nanostructured metal oxides have been treated with an organometallic Pd(II) precursor to prepare Pd-doped metal oxides, which have been tested as catalysts in two different C–C coupling reactions, namely, the coupling reaction between iodobenzene and phenylboronic acid and the double coupling of iodobenzene with 2,6-dibromopyridin. In all cases interesting conversions and yields were observed for the nanostructured metal oxides.

Most of the catalytic systems for C–C coupling reactions are based on homogeneous catalysts which are normally used only once and do not have a sustainable molecular economy, as they cannot be easily separated from the reaction products to be subsequently recycled and used in other catalytic cycles. The alternative use of heterogeneous catalytic systems, which follow better the principles of green chemistry, is of current environmental and industrial interest for C–C coupling reactions. In this context, although heterogeneous C–C coupling catalysis research has a long history focused on the development of palladium nanoparticles, this field still has several drawbacks to overcome and is an area in continuous evolution, which has developed novel systems based on reusable supported palladium nanoparticles or supported palladium complexes with improved catalytic properties. In this review, the recent research developments of novel hybrid nanostructured materials based on silica, titania and alumina as efficient supports for palladium complexes or palladium nanoparticles are revisited, with special regards to synthetic methodology, characterization methods and catalytic performance. The most relevant results concerning the improvement in the environmental impact of the use of palladium complexes or palladium nanoparticles supported onto silica, titania and alumina reported in the last 10 years on Suzuki–Miyaura and other C–C coupling reactions of interest are also described.

Nanotechnology has immensely advanced the field of cancer diagnostics and treatment by introducing potential delivery vehicles as carriers for drugs or therapeutic agents. In due course, mesoporous silica nanoparticles (MSNs) have emerged as excellent vehicles for delivering drugs, biomolecules, and biomaterials, attributed to their solid framework and porosity providing a higher surface area for decorating with various functional ligands. Recently, the metal tin (Sn) has gained huge importance in cancer research owing to its excellent cytotoxicity and ability to kill cancer cells. In the present work, we synthesized MSNs, conjugated them with organotin compounds, and characterized them using various physicochemical techniques. Subsequently, the biological evaluation of MSN (S1), MSN-MP (S2) and tin-conjugated MSNs (S3: MSN-MP-SnPh

A new series of theranostic silica materials based on fibrous silica particles acting as nanocarriers of two different cytotoxic agents, namely, chlorambucil and an organotin metallodrug have been prepared and structurally characterized. Besides the combined therapeutic activity, these platforms have been decorated with a targeting molecule (folic acid, to selectively target triple negative breast cancer) and a molecular imaging agent (Alexa Fluor 647, to enable their tracking both in vitro and in vivo). The in vitro behaviour of the multifunctional silica systems showed a synergistic activity of the two chemotherapeutic agents in the form of an enhanced cytotoxicity against MDA-MB-231 cells (triple negative breast cancer) as well as by a higher cell migration inhibition. Subsequently, the in vivo applicability of the siliceous nanotheranostics was successfully assessed by observing with in vivo optical imaging techniques a selective tumour accumulation (targeting ability), a marked inhibition of tumour growth paired to a marked antiangiogenic ability after 13 days of systemic administration, thus, confirming the enhanced theranostic activity. The systemic nanotoxicity was also evaluated by analyzing specific biochemical markers. The results showed a positive effect in form of reduced cytotoxicity when both chemotherapeutics are administered in combination thanks to the fibrous silica nanoparticles. Overall, our results confirm the promising applicability of these novel silica-based nanoplatforms as advanced drug-delivery systems for the synergistic theranosis of triple negative breast cancer.

Nano-sized materials have shown to have very high potential in anticancer therapy by an adequate tuning of their functionalization and physico-chemical properties. This study is focused on the synthesis and characterization of mesoporous silica nanoparticles (MSN) functionalized with a titanium(IV) or an organotin(IV) compound (therapeutic agents), fluorescein isothiocyanate (image agent) and transferrin (targeting molecule). The analysis of the biological activity of the metallodrug-functionalized systems with and without transferrin has been evaluated and the cell internalization with respect to the presence of the protein has been assessed. The biological results show, as expected, that Sn-based materials are more active than the Ti-based systems with some of the tin-functionalized nanoparticles being almost 50 times more active than carboplatin. In contrast, the cellular uptake seems to be higher in Ti-based materials, which take advantage of the stronger interaction with transferrin to internalize the cells with more effectivity. Finally, a study of vascular endothelial growth factor A (VEGF-A), human fibroblast growth factor 2 (FGF-2) and nuclear factor κβ transcription factor (NF-κβ) show that, specially the Sn-based MSNs, were able to modulate these factors in A2780 cells showing anti-angiogenic effects through VEGF-A and FGF-2, probably due to interaction of the materials with transferrin. S1387181121003644

A series of hybrid catalysts of the type, support-ligand-Pd (Sup-L-Pd), has been prepared and characterized and their activity in C-C coupling (Suzuki-Miyaura), selective oxidations and dehalogenation‑hydrogenation processes studied. The hybrid Sup-L-Pd catalysts are made up of (i) different nano-sized supports, such as halloysite nanotubes (HNTs), SiO2, Al2O3 and mesoporous silica nanoparticles (MSNs), (ii) ligands (L) with N-, S- or P-donor atoms and (iii) different quantities of Pd. Several combinations of support, ligand, and Pd quantity were used to determine the optimal composition of the nanostructured systems for the proposed catalytic reactions. The system based on HNTs functionalized with 2-(diphenylphosphino)ethyltriethoxysilane (PPETS) and 0.25% wt. Pd (HNTs-PPETS-Pd0.25) showed the most promising catalytic behaviour with multifunctional applicability in different catalytic processes and potential reusability. This catalyst gave turnover frequency (TOF) values of up to 155 h−1 in catalytic Suzuki-Miyaura C-C coupling reactions, up to 43 h−1 in selective catalytic oxidations and up to 65 h−1 in dehalogenation‑hydrogenation processes of halogenated aromatic compounds. Furthermore, the system demonstrated in the different catalytic reactions, good recyclability after consecutive cycles with low Pd leaching.

Three different multifunctional nanosystems based on the tethering onto mesoporous silica nanoparticles (MSN) of different fragments such as an organotin-based cytotoxic compound Ph3Sn{SCH2CH2CH2Si(OMe)3} (MSN-AP-Sn), a folate fragment (MSN-AP-FA-Sn), and an enzyme-responsive peptide able to release the metallodrug only inside cancer cells (MSN-AP-FA-PEP-S-Sn), have been synthesized and fully characterized by applying physico-chemical techniques. After that, an in vitro deep determination of the therapeutic potential of the achieved multifunctional nanovectors was carried out. The results showed a high cytotoxic potential of the MSN-AP-FA-PEP-S-Sn material against triple negative breast cancer cell line (MDA-MB-231). Moreover, a dose-dependent metallodrug-related inhibitory effect on the migration mechanism of MDA-MB-231 tumor cells was shown. Subsequently, the organotin-functionalized nanosystems have been further modified with the NIR imaging agent Alexa Fluor 647 to give three different theranostic silica-based nanoplatforms, namely, MSN-AP-Sn-AX (AX-1), MSN-AP-FA-Sn-AX (AX-2), and MSN-AP-FA-PEP-S-Sn-AX (AX-3). Their in vivo potential as theranostic markers was further evaluated in a xenograft mouse model of human breast adenocarcinoma. Owing to the combination of the receptor-mediated site targeting and the specific fine-tuned release mechanism of the organotin metallodrug, the nanotheranostic drug MSN-AP-FA-PEP-S-Sn-AX (AX-3) has shown targeted diagnostic ability in combination with enhanced therapeutic activity by promoting the inhibition of tumor growth with reduced hepatic and renal toxicity upon the repeated administration of the multifunctional nanodrug. The CNIC is supported by MINECO and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). M.F. would like to thank MINECO for the research grant no. SAF2014-59118-JIN co-funded by Fondo Europeo de Desarrollo Regional (FEDER) and COST Action CA1520: “European Network on NMR Relaxometry-EURELAX.” M.F. acknowledges the Comunidad Autonoma de Madrid for research project no. 2017-T1/BIO-4992 (“Atracción de Talento” Action) also cofunded by Universidad Complutense de Madrid. M.F. and K.O.P. are grateful to ICTS-ReDIB. M.M and M.F. are grateful to the Comunidad Autónoma de Madrid and FEDER for the I+D collaborative Programme in Biomedicine NIETO-CM (Project reference B2017-BMD3731). We would also like to thank the Ministerio de Ciencia, Innovación y Universidades of Spain (grants numbers RTI2018-094322-B-I00 and CTQ2017-90802-REDT) for the funding and Dirección General de Investigación e Innovación, Consejería de Educación e Investigación de la Comunidad de Madrid for the predoctoral grant PEJD-2017-PRE/AMB-4047 (M.D.-S.). Sí

A series of copper-functionalized SBA-15 (Santa Barbara Amorphous) materials containing the ligands triethoxysilylpropylmaleamic acid (maleamic) or triethoxy-3-(2-imidazolin-1-yl)propylsilane (imidazoline) have been prepared. The nanostructured silica-based systems SBA-maleamic, SBA-imidazoline, SBA-maleamic-Cu and SBA-imidazoline-Cu were characterized by several methods observing that the functionalization took place mainly inside the pores of the mesoporous system. The antimicrobial behaviour of the synthesized materials against Staphylococcus aureus and Escherichia coli was tested observing a very potent activity of the copper-functionalized systems (minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values for SBA-maleamic-Cu of ca. 31.25 μg/mL, which correspond with ca. 1.13 μg/mL of Cu). A study of the oxidative stress promoted by the synthesized materials showed that the SBA-maleamic-Cu and the SBA-imidazoline-Cu were able to increase the reactive oxygen species (ROS) production in S. aureus by 427% and 373%, respectively, while this increase was slightly lower in E. coli (387 and 324%, respectively). Furthermore, an electrochemical study was carried out in order to determine if these materials interact with lysine or alanine to validate a potential antimicrobial mechanism based on the inhibition of the synthesis of the peptidoglycan of the bacterial wall. Finally, these studies were also performed to determine the potential interaction of the copper-containing materials with glutathione in order to assess if they are able to perturb the metabolism of this tripeptide.

Ionic liquid (IL) assisted syntheses of ultrareactive F-doped mesoporous aggregates of titanium dioxide nanoparticles have been studied using different synthetic methods in order to obtain non-toxic, highly versatile systems able to combine the high photocatalytic activity of the F-doping with a high surface area, to be applied in different catalytic and photocatalytic processes of environmental interest. The synthesized materials were characterized by various techniques, showing that they consist of mesoporous aggregates of F-doped anatase nanoparticles with surface areas of up to ca. 200 m2/g, which, together with the incorporation of ultrareactive (001) anatase facets promoted by doping, made the synthesized titanium dioxide nanomaterials very active in photocatalytic processes. The studies systems showed in the photocatalytic degradation of organic contaminants degradations of up to 96 % of concentrated solutions of methylene blue and common emerging pollutants such as ciprofloxacin (90 % degradation) and naproxen (79 % degradation) under UV light (300 W) in 10 min. In addition, when doped with palladium nanoparticles they became effective heterogeneous catalysts in Suzuki–Miyaura C–C coupling reactions giving good to excellent halide conversions (between 60–99 % for the formation of biphenyl derivatives) and high TOF values (up to 120 h−1) at short reaction times and good degree of recyclability. In addition, the Pd- and Pt-doped systems were also tested in the green process of hydrogen production by methanol photoreforming, showing a good accumulated hydrogen amount of ca. 75 mmol after 400 min with moderate photonic efficiencies of up to ca. 4.1 %.

Nanostructured alumina has been treated under mild conditions with different quantities of [PdCl2(cod)] (cod = 1,5-cyclooctadiene) to promote the formation of supported palladium nanoparticles which have been characterized by XRD, XRF, BET and TEM. The results show that the new hybrid materials, nano-Al2O3-Pd-20 and nano-Al2O3-Pd-50, consist of impregnated palladium nanoparticles onto aggregates of nanoparticles of alumina. The catalytic activity of the hybrid Pd-alumina materials has been tested in Suzuki–Miyaura C–C coupling reactions observing good conversion rates in the reactions of 3-bromoanisole with 4-carboxyphenylboronic acid or 4-vinylphenylboronic acid. The catalytic studies have been extended with experiments investigating the Pd loading influence. Catalyst recyclability tests show a slight decrease in activity after the first cycle in the reaction of 3-bromoanisole with 4-vinylphenylboronic acid. However, subsequent activity remains almost constant after five more consecutive catalytic cycles.

Novel nanomaterials based on doped TiO2 nanoparticles with different morphological, textural and band-gap properties have been synthesized using scalable methods. The influence of synthetic parameters such as titanium source (titanium(IV) isopropoxide and titanium(IV) butoxide), doping quantity (0%, 2% or 5% Zn), acidic solution for the hydrolysis reaction (ascorbic acid, nitric acid) and calcination temperatures (500°C and 600°C) was simultaneously investigated. The obtained nanomaterials were characterized by different methods and photocatalytic tests of methylene blue (MB) degradation under UV-light were conducted to determine their activity. The results revealed that the synthesized nanomaterials are porous aggregates with very high crystallinity and are mainly composed of the anatase phase; although their physical properties vary depending on the different synthetic parameters employed. These changes are able to modify the apparent rate constant of the degradation of MB up to one order of magnitude, indicating, substantial changes in their photoactivity. Hybrid materials TiO2-Pd nanoparticles have also been prepared, characterized and tested for hydrogen production using photocatalytic methanol reforming where supported palladium nanoparticles acted as co-catalyst. Furthermore, the hybrid materials TiO2-Pd nanoparticles were studied in photocatalytic tests of methylene blue degradation under visible LED-light. The results obtained in the production of hydrogen from the photocatalytic reforming of methanol by hybrid materials suggest that the reported hybrid systems could be suitable photocatalysts for future sustainable hydrogen production upon tuning of the morphological, textural and band gap energy properties to allow processes to be carried out under visible light.

Two different silica based (MSU-2 and MCM-41) curcumin loaded mesoporous materials V3 and V6 were synthesized and characterized by several physico-chemical techniques. Release kinetic study revealed the slow and sustained release of curcumin from those materials in blood simulated fluid (pH: 7.4). The materials V3 and V6 were found to be biocompatible in non-cancerous CHO cell line while exhibiting significant cytotoxicity in different cancer cells (human lung carcinoma cells: A549, human breast cancer cells: MCF-7, mouse melanoma cells: B16F10) compared to pristine curcumin indicating the efficacy of the mesoporous silica materials based drug delivery systems (DDSs). The generation of intracellular reactive oxygen species (ROS) and down regulation of anti-apoptotic protein leading to the induction of apoptosis were found to be the plausible mechanisms behind the anti-cancer activity of these DDSs. These results suggest that curcumin-loaded drug delivery system may be successfully employed as an alternative treatment strategy for cancer therapeutics through a nanomedicine approach in near future.

Nanotechnology has shown great promise in unraveling several important issues of conventional anticancer chemotherapy. Expectations project that a new generation of effective cancer therapies will be developed with enormous potential to overcome the biological, biophysical and biomedical obstacles that the human body enacts against standard chemotherapeutic treatments. Generally, nanostructures protect the entombed drug molecules from degradation in blood, allowing their safe and unimpaired delivery to specific target sites in the body. Nanostructured macromolecular systems such as curcubit[ n ]urils, cyclodextrins, liposomes, lipid nanocapsules, proteins, polynuclear organometallic compounds, carbon nanotubes, polymeric nanoparticles and ceramic materials have shown great potential in facilitating the administration of potent anticancer metallodrugs. The uniqueness of these nanostructured materials lies in their suitability for functionalization with small molecule drugs. Recently, there has been a great deal of interest among oncologists and medicinal chemists in functionalizing nanostructured materials with anticancer metallodrugs to ensure better administration. In view of these facts, the state-of-art of nanostructured materials functionalized with metallodrugs as anticancer agents is described in this review. The functionalization of several classes of metal complexes including platinum and non-platinum compounds is also addressed. Special focus is given to the co-delivery of metallodrugs within nanostructures. Toxicity of nanomaterials is discussed and the associated concerns are also highlighted. Finally, the current challenges and the future perspectives of metallodrug functionalization have been commented upon.

Mesoporous silica nanoparticles (MSN) have been functionalized with the polyamino ligand N1-(3-trimethoxysilylpropyl)diethylenetriamine to give the material MSN-DETATMS (M1). The reaction of M1 with the diphenyltin(IV) compound Sn1 [obtained previously from the reaction of (3-glycidyloxypropyl)trimethoxysilane and diphenyltin(IV) dichloride in the presence of two equivalents of sodium hydroxide] in a quantity to obtain a theoretical 10% wt Sn/SiO2, gave the material MSN-DETATMS-O2-SnPh2 (M2). Alternatively, M1 was reacted with folic acid to achieve the incorporation of the folate fragment via formation of an amido bond MSN-DETATMS-FA (M3) and subsequently with Sn1 to give the tin-functionalized material MSN-DETATMS-FA-O2-SnPh2 (M4). M1‒M4 have been characterized by several methods such as infrared spectroscopy (FT-IR), powder X-ray diffraction (XRD), X-ray fluorescence (XRF), solid-state NMR spectroscopy, nitrogen adsorption-desorption isotherms, electrochemical methods, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). All the synthesized nanomaterials have been tested in vitro against a wide variety of cancer and non-cancer cells in order to determine different aspects of their antitumour effects such as cell uptake, cell death, cell migration and cell invasion, to observe whether the incorporation of folate fragments may increase the cell uptake and selectivity towards cancer cells, thus increasing their potential applicability in future chemotherapeutic approaches.

The immobilization of two titanocene complexes on SBA-15 has been accomplished following post-synthetic procedures. The ionic liquid, 1-methyl-3-[(triethoxysilyl)propyl]imidazolium chloride, has also been incorporated into the titanium containing materials to determine its influence on the interaction with molecules of biological interest. Cyclic voltammetry has been used to study the influence of the ionic liquid on the mechanism of reduction of titanocene derivatives. The interaction of titanocene and titanocene/ionic liquid-containing mesoporous silica SBA-15 materials, with molecules of biological interest associated with important processes of metallodrug action against cancer cells, has been studied. Thus, we have carried out hydrolysis experiments on the materials functionalized with titanocene derivatives in physiological media to determine their stability and the interaction with serum/transport proteins such as transferrin and BSA and with target molecules such as guanosine, single-stranded DNA and double-stranded DNA by means of solid state voltammetry techniques. A qualitative analysis of the data based on peak current and reduction potential value changes of the couple Ti(iv)/Ti(iii) in the presence of biomolecules at physiological pH, has revealed that grafted titanocene complexes show higher affinity for serum/transport proteins than for nucleic acids, indicating that the transport steps to the cells may be easier than the subsequent attack on DNA.

The synthesis of the ether-substituted group 4 metallocene complexes [Ti(η5-C5H5)(η5-C5H4{CMeRCH(OMe)2})Cl2] (R = Me (4), Ph (5)) and [M(η5-C5H4{CMeRCH(OMe)2})2Cl2] (M = Ti, R = Me (6), Ph (7); M = Zr, R = Me (8), Ph (9)) is reported. In addition, the titanocene derivatives 4–7 have been supported on the mesoporous silica-based material KIT-6, giving the functionalized materials K4–K7, respectively. All compounds and materials have been characterized by different analytical techniques such as solution NMR spectroscopy, mass spectrometry, elemental analysis, solid-state multinuclear NMR spectroscopy, IR spectroscopy, N2 adsorption–desorption isotherms, X-ray fluorescence and diffraction, SEM, and TEM. Additionally, the molecular structures of the zirconocene derivative 8 and the hydrolysis product [Ti(η5-C5H5)(η5-C5H4{CMe2COO})Cl] (4a) of titanocene complex 4 have been determined by X-ray diffraction studies. The structure of 4a reveals a five-membered metallacyclic arrangement. The ether-substituted titan...

A series of cytotoxic titanocene derivatives have been immobilized onto nanostructured silica-based materials using two different synthetic routes, namely, (i) a simple grafting protocol via protonolysis of the Ti-Cl bond; and (ii) a tethering method by elimination of ethanol using triethoxysilyl moieties of thiolato ligands attached to titanium. The resulting nanostructured systems have been characterized by different techniques such as XRD, XRF, DR-UV, BET, SEM, and TEM, observing the incorporation of the titanocene derivatives onto the nanostructured silica and slight changes in the textural features of the materials after functionalization with the metallodrugs. A complete biological study has been carried out using the synthesized materials exhibiting moderate cytotoxicity in vitro against three human hepatic carcinoma (HepG2, SK-Hep-1, Hep3B) and three human colon carcinomas (DLD-1, HT-29, COLO320) and very low cytotoxicity against normal cell lines. In addition, the cells' metabolic activity was modified by a 24-h exposure in a dose-dependent manner. Despite not having a significant effect on TNFα or the proinflammatory interleukin 1α secretion, the materials strongly modulated tumor necrosis factor (TNF) signaling, even at sub-cytotoxic concentrations. This is achieved mainly by upregulation of the TNFR1 receptor production, something which has not previously been observed for these systems., We gratefully acknowledge financial support from FEDER and the Ministerio de Economía y Competitividad, Spain (grant no. CTQ2015-66164-R) and the Romanian UEFISCDI Exploratory Research Project PN-III-P4-ID-PCE-2016-0870, IMPRESS.We would also like to thank Universidad Rey Juan Carlos and Banco de Santander for supporting our Research Group of Excellence QUINANOAP. Finally, we thank D. Pérez for valuable discussion and S. Carralero and C. Forcé for their assistance with solid-state NMR experiments.

Heterogeneous recyclable catalysts in Suzuki-Miyaura C-C coupling reactions are of great interest in green chemistry as reusable alternatives to homogeneous Pd complexes. Considering the interesting properties of fluorinated compounds for the pharmaceutical industry, as precursors of novel materials, and also as components of liquid crystalline media, this present study describes the preparation of different fluorinated biphenyl derivatives by Suzuki-Miyaura coupling reactions catalyzed by a heterogeneous system (G-COOH-Pd-10) based on Pd nanoparticles supported onto COOH-modified graphene. The catalytic activity of the hybrid material G-COOH-Pd-10 has been tested in Suzuki-Miyaura C–C coupling reactions observing excellent versatility and good conversion rates in the reactions of phenylboronic acid, 4-vinylphenylboronic acid, 4-carboxyphenylboronic acid, and 4-fluorophenylboronic acid with 1-bromo-4-fluorobenzene. In addition, the influence of the arylbromide has been studied by carrying out reactions of 4-fluorophenylboronic acid with 1-bromo-2-fluorobenzene, 1-bromo-3-fluorobenzene, 1-bromo-4-fluorobenzene, 2-bromo-5-fluorotoluene, and 2-bromo-4-fluorotoluene. Finally, catalyst recyclability tests show a good degree of reusability of the system based on G-COOH-Pd-10 as the decrease in catalytic activity after five consecutive catalytic cycles in the reaction of 1-bromo-4-fluorobenzene with 4-florophenylboronic acid at 48 hours of reaction is lower than 8% while in the case of reactions at three hours the recyclability of the systems is much lower., We gratefully acknowledge financial support from the Ministerio de Economía y Competitividad, Spain (Grant no. CTQ2015-66164-R). We would also like to thank Universidad Rey Juan Carlos and Banco de Santander for supporting our Research Group of Excellence QUINANOAP. We would also like to thank Isfahan University of Technology for the partial financial support of the research stay of R.S.E.

The ansa indenyl ligand precursors CH2CH2CH2(C9H6R)2 (R = Me (7), Et (8), Pr (9)) have been prepared by the reaction of the corresponding lithium indene, Li(C9H6R-1) (R = Me (4), Et (5), Pr (6)), with 1,3-dibromopropane. Compounds 7–9 were converted, by the reaction with butyllithium, to the dilithium compounds, Li2{CH2CH2CH2(C9H5R-3)2} (R = Me (10), Et (11), Pr (12)). The three carbon atom bridge ansa-bis(indenyl)zirconium complexes, [Zr{CH2CH2CH2(η5-C9H5R-3)2}Cl2] (R = Me (13), Et (14) Pr (15)) were synthesized from the reaction of 10–12 with zirconium tetrachloride. Compounds 13–15 have been tested as homogeneous catalysts in the polymerization of ethylene. The molecular structures of 14 and 15 have been determined by single-crystal X-ray diffraction studies.

The alkenyl substituted zirconocene complexes, [Zr(η5-C5H4{CMeRCH2CH2CH = CMe2})2Cl2] (R = Me (1), Ph (2) were prepared from the reaction of the lithium derivative Li(C5H4{CMeRCH2CH2CH = CMe2}) (R = Me, Ph) with zirconium tetrachloride. The bulky alkyl substituted cyclopentadienyl ligand precursor was prepared as its fulvene derivative (C5H4) = CMeCH2CHMe2 (3) via the reaction of cyclopentadiene with 4-methyl-2-pentanone and then converted to Li(C5H4{CMe2CH2CHMe2}) (4) via nucleophilic attack of LiMe. The reaction of 4 with [TiCl4(THF)2] and ZrCl4 gave the metallocene complexes [M(η5-C5H4{CMe2CH2CHMe2})2Cl2] (M = Ti (5), Zr (6)), respectively. The ansa-ligand precursor, SiMe2(C5HMe4)(C5H4{CMe2CH2CHMe2}) (7), was prepared via the reaction of 4 with SiMe2(C5HMe4)Cl and subsequently converted to its dilithium derivate, Li2(Me2Si(C5Me4)(C5H3{CMe2CH2CHMe2})) (8), using n-butyllithium. The ansa-zirconocene complex, [Zr{Me2Si(η5-C5Me4)(η5-C5H3{CMe2CH2CHMe2})}Cl2] (9), was synthesized by the reaction of 8 with zirconium tetrachloride. Compounds 1–9 were characterized by 1H and 13C{1H} NMR spectroscopy. In addition, the molecular structures of 5, 6 and 9 were determined by single crystal X-ray diffraction studies. The metallocene complexes have been tested as catalyst (with co-catalyst MAO) in the polymerization of ethylene where the substituents on the cyclopentadienyl ligand have a direct influence on the catalytic activity.

This article reviews the use of silica, alumina and calcium phosphate-based nanostructured materials with biomedical applications. A short introduction on the use of the materials in Science, Nanotechnology and Health is included followed by a revision of each of the selected materials. A description of the principal synthetic methods used in the preparation of the materials in nanostructured form is included. The most widely used applications in biomedicine are reviewed including, for example drug-delivery, bone regeneration, imaging, sensoring amongst others. Finally, a short description of the toxicity and cytotoxicity associated with each of the materials of this revision is presented. This short literature revision serves to demonstrate the very promising future ahead of nanosystems based on silica, alumina and calcium phosphate for biological and biomedical applications.

Several titanocene(IV) complexes with different carboxylato ligands such as 3-methoxyphenylacetic acid (3-mpa-COOH), 4-methoxyphenylacetic acid (4-mpa-COOH), 1,4-benzodioxane-6-carboxylic acid (bdo-COOH), 2,5-dimethyl-3-furoic acid (dmf-COOH) and 4-(4-morpholinyl)benzoic acid (mbz-COOH) have been synthesized. All the novel titanocene(IV) carboxylate complexes have been characterized by traditional spectroscopic methods, with the molecular structures of [Ti(η5-C5H5)2(OOC-dmf)2] (7) and [Ti(η5-C5H4Me)2(OOC-dmf)2] (8) being determined by single crystal X-ray diffraction studies. Complexes were tested against the tumour cell line A2780 (ovarian cancer) and showed notable cytotoxicity. In addition, a study of the interaction of 7 and 8 with DNA (probably one of the biological target-molecules of the titanocene derivatives) monitored by UV–visible spectroscopy has been carried out.

The synthesis, characterization and the cytotoxic studies of several naphthyl-substituted titanocene complexes, [Ti(η 5 –C 5 H 5 ){η 5 –C 5 H 3 R(CHR’(C 10 H 7 ))}Cl 2 ] (R = H, R′ = Me ( 8 ), Ph ( 9 ); R = SiMe 3 , R′ = Me ( 10 ), Ph ( 11 )), are reported. In addition, the molecular structure of 9 has been determined by single-crystal X-ray diffraction studies. The cytotoxic activity of 9 – 11 has been examined against five human tumour cell lines: 8505C (anaplastic thyroid carcinoma), A549 (lung adenocarcinoma), A2780 (ovarian cancer), DLD-1 (colon carcinoma) and FaDu (head and neck carcinoma). Complex 11 showed the highest cytotoxic activity on all studied cell lines (IC 50 values from 35.65 ± 4.95 to 69.02 ± 1.67 μM). All compounds are more active than reference compound [Ti(η 5 –C 5 H 5 ) 2 Cl 2 ] on all cell lines (except complex 8 against A549) leading to the conclusion that the presence of different substituents on the cyclopentadienyl ring may improve cytotoxicity of titanocene dichloride.

Dehydrated MCM-41 (S 1) was functionalized under nitrogen with 3-chloropropyltriethoxysilane (CPTS) and 3-aminopropyltriethoxysilane (APTS) by grafting in toluene at 80 °C over 48 h to give the corresponding materials S 2 and S 3, respectively. Subsequently, S 2 and S 3 were suspended in methanol and reacted in a nitrogen atmosphere with betulinic acid (BA) for 48 h at 65 °C (in the presence of the triethylamine of S 2) to give the BA-functionalized materials S 4 and S 5. All materials studied were characterized by powder X-ray diffraction, X-ray fluorescence, nitrogen gas sorption, multinuclear MAS NMR spectroscopy, thermogravimetry, UV spectroscopy, IR, SEM, and TEM. To study the release of BA, S 4 and S 5 were suspended in solutions simulating various body pH conditions (pH 7.4, 5.5, and 3.0). Results of the quantification of BA release by HPLC for S 4 show a pH-dependent and very slow BA release following a logarithmic tendency, while S 5 behaves differently, also pH-dependent but, in this case, fast release of BA which requires only days for total release of the therapeutic compound. In addition, the cytotoxic activity of all synthesized materials against various cancer cell lines was studied. The results show the absence of an antiproliferative effect on the surfaces without BA S 1–S 3, while an antiproliferative effect was observed with S 4 and S 5 and was attributed to the release of BA in the medium.

Titanocene dichloride [Ti(η 5 -C 5 H 5 ) 2 Cl 2 ] ( 1 ), has been grafted onto dehydrated hydroxyapatite (HAP), Al 2 O 3 and two mesoporous silicas MSU-2 (Michigan State University Silica type 2) and HMS (Hexagonal Mesoporous Silica), to give the novel materials HAP/[Ti(η 5 -C 5 H 5 ) 2 Cl 2 ] ( S1 ) (1.01 wt.% Ti), Al 2 O 3 /[Ti(η 5 -C 5 H 5 ) 2 Cl 2 ] ( S2 ) (2.36 wt.% Ti), HMS/[Ti(η 5 -C 5 H 5 ) 2 Cl 2 ] ( S3 ) (0.75 wt.% Ti) and MSU-2/[Ti(η 5 -C 5 H 5 ) 2 Cl 2 ] ( S4 ) (0.74 wt.% Ti), which have been characterized by powder X-ray diffraction, X-ray fluorescence, nitrogen gas sorption, multinuclear magic angle spinning NMR spectroscopy, IR spectroscopy, thermogravimetry analysis, UV spectroscopy, scanning electronic microscopy and transmission electronic microscopy. The cytotoxicity of the titanocene-functionalized materials toward human cancer cell lines from five different histogenic origins: 8505 C (anaplastic thyroid cancer), A253 (head and neck cancer), A549 (lung carcinoma), A2780 (ovarian cancer) and DLD-1 (colon cancer) has been determined. M 50 values (quantity of material needed to inhibit normal cell growth by 50%) and Ti-M 50 values (quantity of anchored titanium needed to inhibit normal cell growth by 50%) indicate that the activity of S1 – S4 against studied human cancer cells depended on the surface type as well as on the cell line. In addition, studies on the titanocene release and the interaction of the materials S1 – S4 with DNA show that the cytotoxic activity may be due to particle action, because no release of titanium complexes has been observed in physiological conditions, while electrostatic interactions of titanocene-functionalized particles with DNA have been observed.

The reaction of 2,6-dimethoxypyridine-3-carboxylic acid (DMPH) with different precursors [Ti(η5-C5H5)2Cl2], [Ti(η5-C5H4Me)2Cl2], [Ti(η5-C5H4SiMe3)(η5-C5H5)Cl2], [Ti(η5-C5Me5)Cl3], SnMe3Cl and GatBu3 yielded the complexes [Ti(η5-C5H5)2(DMP-κO)2] (1), [Ti(η5-C5H4Me)2(DMP-κO)2] (2), [Ti(η5-C5H4SiMe3)(η5-C5H5)(DMP-κO)2] (3), [Ti(η5-C5Me5)(DMP-κ2O,O′)3] (4), [SnMe3(μ-DMP-κO:κO′)]∞ (5), and [GatBu2(μ-DMP-κO:κO′)]2 (6). 1–6 have been characterized by spectroscopic methods and the molecular structure of the complexes 1, 2, 3, 5 and 6 have been determined by X-ray diffraction studies. The cytotoxic activity of 1–6 was tested against the tumour cell lines human adenocarcinoma HeLa, human myelogenous leukaemia K562, human malignant melanoma Fem-x and human breast carcinoma MDA-MB-361. The results of this study show a higher cytotoxicity of the tin(IV) and gallium(III) derivatives in comparison to their titanium(IV) counterparts. Furthermore, the different titanium compounds showed differences in their cytotoxicities with a higher activity of complex 4 (mono-(cyclopentadienyl) derivative) compared to that of 1–3 (bis-(cyclopentadienyl) complexes). A qualitative UV–vis study of the interactions of these complexes with DNA has also been carried out.

The carboxylate compounds [Ti(η5-C5H5)(η5-C5H4{CMe2(CH2CH2CHCH2)})(O2CCH2SXyl)2] (2; Xyl = 3,5-Me2C6H3) and [Ti(η5-C5H5)(η5-C5H4{CMe2(CH2CH2CHCH2)})(O2CCH2SMesl)2] (3; Mes 1 = 2,4,6-Me3C6H2) were synthesized by the reaction of [Ti(η5-C5H5)(η5-C5H4{CMe2(CH2CH2CHCH2)})Cl2] (1) with 2 equivalents of xylylthioacetic acid or mesitylthioacetic acid, respectively. Compounds 2 and 3 were characterized by spectroscopic methods. The cytotoxic activity of 1–3 was tested against human tumor cell lines from four different histogenic origins—8505C (anaplastic thyroid cancer), DLD-1 (colon cancer) and the cisplatin sensitive A253 (head and neck cancer) and A549 (lung carcinoma)—and compared with those of the reference complex [Ti(η5-C5H5)2Cl2] (R1) and cisplatin. Surprisingly, the cytotoxic activities of the carboxylate derivatives were lower than those of their corresponding dichloride analogue (1). However, complexes 1–3 were more active than titanocene dichloride against all the studied cells with the exception of complex 2 against A253 and A549 cell lines. DNA-interaction tests were also carried out. Solutions of all the studied complexes were treated with different concentrations of fish sperm DNA, observing modifications of the UV spectra with intrinsic binding constants of 2.99 × 105, 2.45 × 105, and 2.35 × 105M−1 for 1–3. Structural studies based on density functional theory calculations of 2 and 3 were also carried out. Copyright © 2010 John Wiley & Sons, Ltd.

The triphenyltin(IV) carboxylate compounds [{SnPh3(O2CCH2SXyl)}∞] (1) (Xyl = 3,5-Me2C6H3) and [{SnPh3(O2CCH2SMes)}∞] (2) (Mes = 2,4,6-Me3C6H2) have been synthesized by the reaction of SnPh3Cl with one equivalent of xylylthioacetic acid or mesitylthioacetic acid, respectively. 1 and 2 have been characterized by spectroscopic methods. The cytotoxic activity of 1 and 2 was tested against human tumour cell lines from four different histogenic origin: 8505C (anaplastic thyroid cancer), DLD-1 (colon cancer) and the cisplatin sensitive A253 (head and neck cancer) and A549 (lung carcinoma) and compared with those of the reference complex cisplatin. Interestingly, the cytotoxic activities of the carboxylate derivatives were higher than those of cisplatin against all the studied cells. DNA-interaction tests have been also carried out. Solutions of all the studied complexes have been treated with different concentrations of fish sperm DNA (FS-DNA), observing modifications of the UV spectra with intrinsic binding constants of 1.68 × 105 and 1.02 × 105, M−1 for 1 and 2, respectively. In addition, the molecular structure of 2 has been determined by single crystal X-ray diffraction studies, observing that 2 consists of a 1-D coordination polymer in which the tin atoms present a five-coordinated geometry by coordination of two different oxygen atoms of two crystallographically dependent carboxylato ligands.

Four different titanocene complexes, [Ti(η5-C5H5)2Cl2] (1), [Ti(η5-C5H5)(η5-C5H4Pri)Cl2] (2), [Ti(η5-C5H5)(η5-C5H4But)Cl2] (3) and [Ti(η5-C5H5){η5-C5H3(SiMe3)2}Cl2] (4), have been grafted onto dehydroxylated MCM-41 to give the novel materials MCM-41/[Ti(η5-C5H5)2Cl2] (S1), MCM-41/[Ti(η5-C5H5)(η5-C5H4Pri)Cl2] (S2), MCM-41/[Ti(η5-C5H5)(η5-C5H4But)Cl2] (S3) and MCM-41/[Ti(η5-C5H5){η5-C5H3(SiMe3)2}Cl2] (S4), which have been characterized by powder X-ray diffraction, X-ray fluorescence, nitrogen gas sorption, multinuclear MAS NMR spectroscopy, thermogravimetry, UV spectroscopy, SEM and TEM. The cytotoxicity of the non-functionalized MCM-41 and S1–S4 toward human cancer cell lines, such as adenocarcinoma HeLa, human myelogenous leukemia K562 and human malignant melanoma Fem-x, has been studied. Additional studies of the toxicity of these materials on stimulated and non-stimulated peripheral blood mononuclear cells (PBMC + PHA and PBMC − PHA; i.e. normal immunocompetent cells) have been also carried out. M50 values (quantity of material needed to inhibit normal cell growth by 50%) of the studied surfaces are reported observing that non-functionalized MCM-41 did not show notable antiproliferative activity, while the functionalized surfaces S1–S4 were active against all of the studied human cancer cells. The cytotoxic activities of surfaces S1–S3 were very similar on all the studied cancer cells, however, S4 showed M50 values that indicate the highest activity of all the analyzed materials on all the studied cells, being two to three times more cytotoxic than S1–S3. The same tendency in the cytotoxic activity of the metal complexes 1–3 compared with 4 was observed. Taking into account that all the studied surfaces had a very similar titanium content, the activity of these surfaces strongly depends on the grafted titanocene complex (1–4). This phenomenon indicates that, in contrast with that observed by other authors, the cytotoxicity of the studied materials may be due to action of the released metal complex and is probably not due to the particle action.

The organotin compounds, [SnPh 3 (C 5 H 4 R)] (R = Bu t ( 1 ), CMe 2 (CH 2 CH 2 CH CH 2 ) ( 2 )) and [SnPh 3 (C 5 Me 4 R)] (R = H ( 3 ), SiMe 3 ( 4 )), were prepared by the reaction of SnPh 3 Cl with the lithium derivative of the corresponding cyclopentadiene. 1 – 4 have been characterized by multinuclear NMR spectroscopy ( 1 H, 13 C{ 1 H} and 119 Sn{ 1 H}). In addition, the molecular structures of 1 , 2 and 4 were determined by single-crystal X-ray diffraction studies. The cytotoxic activity of the organotin(IV) complexes ( 1 – 4 ) was tested against human tumour cell lines 8505C anaplastic thyroid cancer, A253 head and neck tumour, A549 lung carcinoma, A2780 ovarian cancer, DLD-1 colon carcinoma. Compounds 1 – 4 present higher activities than cisplatin in all the studied cells. The highest sensitivity of the synthesized tin(IV) complexes was observed against A2780 ovarian cancer and DLD-1 colon carcinoma. Complex 3 presents the highest cytotoxic activity of all the studied complexes in all the cancer cells, with IC 50 values from 0.037 to 0.085 μM, however, its trimethylsilyl-substituted analogue ( 4 ), showed the lowest activity against all the studied cells with IC 50 values from 0.163 to 0.351 μM. Complexes 1 and 2 presented very similar activities on all the cancer cells (IC 50 values from 0.044 to 0.119 μM).

The alkenyl substituted fulvene compound, (C5H4) CMe(CH2CH2CH CMe2) (1), reacts with one equivalent of LiMe to give the lithium derivative Li{C5H4(CMe2CH2CH2CH CMe2)} (2). The reaction of 2 with Me2Si(C5Me4H)Cl gave the ansa-ligand precursor Me2Si(C5Me4H)(C5H4(CMe2CH2CH2CH CMe2)) (3), which after the subsequent reaction with 2 equivalents of LiBun yielded the dilithium salt Li2{Me2Si(C5Me4)(C5H3(CMe2CH2CH2CH CMe2))} (4). The alkenyl-substituted zirconocene complex [Zr{Me2Si(η5-C5Me4)(η5-C5H3(CMe2CH2CH2CH CMe2))}Cl2] (5) was synthesized by the equimolar reaction of 4 and ZrCl4. 5 was characterized by spectroscopic methods and by single crystal X-ray diffraction studies. The zirconocene compound 5 has been tested as a catalyst in the polymerization of ethylene at different temperatures and Al:Zr ratios, and also in the co-polymerization of ethylene and 1-octene, observing modest co-monomer incorporations. In addition, the cytotoxic activity of 5 was tested against tumour cell lines 8505C anaplastic thyroid cancer, A253 head and neck tumour, A549 lung carcinoma, A2780 ovarian cancer and DLD-1 colon carcinoma. Complex 5 showed the best cytotoxic activity on A2780 ovarian cancer (IC50 value of 36.8 ± 5.9 μM). This represents the highest reported cytotoxic activity of a zirconocene complex on A2780 ovarian cancer. In addition, the cytotoxic activities of 5, have been compared with those obtained using cisplatin.

The alkenyl-substituted titanocene complex [Ti(η5-C5H5)(η5-C5H4{CMe2(CH2CH2CH CH2)})Cl2] (1) has been synthesized and characterized using traditional methods. The reaction of 1 with 9-BBN gave the boryl substituted complex [Ti(η5-C5H5)(η5-C5H4{CMe2(CH2CH2CH2CH2BC8H14)})Cl2] (2). The cytotoxic activity of 1 and 2 was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, human breast carcinoma MDA-MB-361 and normal immunocompetent cells peripheral blood mononuclear cells PBMC and compared with those of the reference complexes [Ti(η5-C5H5)2Cl2] (R1), [Ti(η5-C5H4Me)2Cl2] (R2) and [Ti(η5-C5H5)(η5-C5H4SiMe3)Cl2] (R3). Complex 1 showed higher cytotoxic activities on HeLa, Fem-x and K562 (IC50 values from 96.6 ± 3.4 to 149.2 ± 2.9 μM) than the reference complexes R1, R2 and R3 which presented IC50 values from 173.3 ± 6.0 to >200 μM. On the other hand, boryl substituted complex 2, present slightly lower cytotoxic activities than 1 on HeLa, Fem-x and K562 (IC50 values from 155.6 ± 5.5 to 167.9 ± 4.2 μM). However, 2 was the most active of the studied complexes against MDA-MB-361 (IC50 value of 161.1 ± 0.1 μM). Structural studies based on DFT calculations of 1 and 2 have also been carried out in order to gain a possible insight into the relationship between metal complex structure and cytotoxicity.

An MCM-41 has been modified by grafting several zirconocene complexes to give new materials potentially active in the polymerization of α-olefins. These materials have been activated by the cocatalyst MAO, to generate the catalysts MCM-41/metallocene/MAO (metallocene = [Zr(η 5 -C 5 H 5 ) 2 Cl 2 ] ( 1 ), [Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 4 )}Cl 2 ] ( 2 ) and [Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 3 Bu t )}Cl 2 ] ( 3 )). The resulting functionalized ordered mesoporous silica samples ( 1 – 3 ) were tested as catalysts in the polymerization of ethylene and compared with both the homogeneous system analogues and the functionalized silica derivatives SG/metallocene/MAO (SG = silica gel; metallocene = [Zr(η 5 -C 5 H 5 ) 2 Cl 2 ] ( 4 ), [Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 4 )}Cl 2 ] ( 5 ) and [Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 3 Bu t )}Cl 2 ] ( 6 )). The metallocenes 2 and 3 have been characterized by 13 C-CP MAS NMR and 29 Si MAS NMR spectroscopy. The structure and surface properties of MCM-41/[Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 4 )}Cl 2 ] and MCM-41/[Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 4 )}Cl 2 ]/MAO systems have been studied by X-ray diffractometry, nitrogen adsorption–desorption isotherms measurement and thermogravimetry. The grafting of the metallocene complexes, activation with MAO and subsequent polymerization reaction have been followed by an FT-IR “in situ” study. Scanning electron microscopy and transmission electron microscopy have been used to show the morphology of the heterogeneous catalysts as well as the resulting polyethylene obtained.

The ansa-titanocene complexes, [Ti{Me2Si(η5-C5Me4)(η5-C5H3R)}Cl2] (R = Me (5), iPr (6), tBu (7), SiMe3 (8)), were obtained from the reaction of Li2{Me2Si(C5Me4)(C5H3R)} (R = Me (1), iPr (2), tBu (3), SiMe3 (4)) with [TiCl4(THF)2], respectively. Compounds 5–8 have been tested as catalysts in the polymerization of ethylene and compared with the ansa-titanocene complexes [Ti{Me2Si(η5-C5H4)2}Cl2] and [Ti{Me2Si(η5-C5Me4)(η5-C5H4)}Cl2]. The resulting polyethylene showed molecular weights of about 200 000 g mol−1 and polydispersity values of approximately 3. In addition, the molecular structure of 6 has been determined by single crystal X-ray diffraction studies.

The relationship between polymer chain topology, i.e. long chain branching (LCB), and rheological properties in polyolefins obtained using single-site catalysts has been the topic of major scientific activity since the late 1990s [1–14]. Indeed, melt-state rheological measurements are being considered as one of the most sensitive methods for detecting sparse LCB in polyethylene (PE) [1, 15]. For example the flow activation energy, Ea, related to the temperature dependence of viscoelastic properties, is altered by the presence of LCB, and the cross-point frequency between storage and loss moduli, xx, and the crosspoint modulus, Gx, are also very sensitive features to the molecular architecture [16–18]. In this context, the study of these properties can give us information about the relationship between polymer chain topology and catalyst structure. In this work, a set of PE samples was synthesized using different metallocene catalysts. The main objective is to find relationships between chemical structure of the catalysts and polymer chain architecture by rheological testing. This is an interesting task as there is still a lack of information in the literature concerning how the catalyst structure affects the creation of LCB during polymerization [15]. The PE samples were synthesized using the catalysts shown in Table 1, together with MAO as co-catalyst. The synthesis of the samples was carried out under the same experimental conditions: a reactor temperature of 20 C, an ethylene pressure of 2 bar, 3 9 10 mol L of metallocene concentration, and a molar ratio MAO (methyl aluminoxane)/metallocene of 3,000 [17–21]. The metallocene catalysts were prepared using synthetic protocols that we have previously reported [20, 21]. The molecular properties of the polymer samples obtained by size exclusion chromatography analysis are listed in Table 1. The details about the experimental procedures are described elsewhere [18, 19]. It has been very difficult to estimate the molecular features in the case of C4 sample, probably due to extremely high molecular weight. In this case we have estimated molecular weight and polydispersity index by rheological methods. The materials were stabilized with 1.0 wt.% Irganox 1010 to avoid degradation at high temperatures. The rheological measurements were carried out using parallel plate geometry (15 mm diameter). Frequency sweeps in the linear viscoelastic regime were performed with a Bohlin CVO rheometer in the angular frequency range between 0.006 and 60 rad s. The linear viscoelastic regime has been located by previous strain sweeps. The measurements have been performed in the temperature range between 145 and 190 C and the time-temperature superposition principle (TTSP) applied to a reference temperature of T0 = 190 C. From these results, the characteristic features described above (Ea, xx, and Gx) have been obtained for the materials under study (see Table 1). The material labeled as A0 has been synthesized by using the [Zr(g-C5H5)2Cl2] catalyst (A), which is the simplest structural fragment used in this study. This catalyst has been previously reported to produce LCB [2, 14]. The sample shows a very high Ea value and a significant elastic character, in spite of the very narrow molecular J. F. Vega (&) J. Martinez-Salazar Departamento de Fisica Macromolecular, Instituto de Estructura de la Materia, CSIC, Serrano 113 bis, 28006 Madrid, Spain e-mail: imtv477@iem.cfmac.csic.es

The ansa -bis(cyclopentadiene) compounds, Me 2 Si(C 5 HPh 4 )(C 5 H 4 R) (R = H ( 2 ); Bu t ( 3 )), have been prepared by the reaction of C 5 HPh 4 (SiMe 2 Cl) ( 1 ) with Na(C 5 H 5 ) or Li(C 5 H 4 Bu t ), respectively, and transformed to the di-lithium derivatives, Li 2 {Me 2 Si(C 5 Ph 4 )(C 5 H 3 R)} (R = H ( 4 ); Bu t ( 5 )), by the action of n -butyllithium. The ansa -zirconocene complexes, [Zr{Me 2 Si(η 5 -C 5 Ph 4 )(η 5 -C 5 H 3 R)}Cl 2 ] (R = H ( 6 ); Bu t ( 7 )), were synthesized from the reaction of ZrCl 4 with 4 or 5 , respectively. Compounds 6 and 7 have been tested in the polymerization of ethylene and compared with their methyl-substituted analogues, [Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 3 R)}Cl 2 ] (R = H ( 8 ); Bu t ( 9 )). Whilst 8 and 9 are catalytically active, the tetraphenyl-substituted complexes 6 and 7 proved to be inactive in the polymerization of ethylene. This phenomenon has been explained by DFT calculations based on the reaction intermediates in the polymerization processes involving 6 and 7 , which showed that the extraction of a methyl group from the zirconocene complex to form the cationic active specie is endothermic and therefore unfavourable.

The zirconocene complexes [Zr(η 5 -C 5 H 5 ){η 5 -C 5 H 4 -(CMe 2 CH 2 CH 2 CH=CH 2 )}Cl 2 ] (4) and [Zr{η 5 -C 5 H 4 (CMe 2 -CH 2 CH 2 CH=CH 2 )} 2 Cl 2 ] (5) were synthesised from the reaction of the lithium derivative [Li{C 5 H 4 (CMe 2 CH 2 -CH 2 CH=CH 2 )}] (1) with [Zr(η 5 -C 5 H 5 )Cl 3 ) or ZrCl 4 , respectively. The ansa-zirconocene complex [Zr{Me 2 Si(η 5 -C 5 Me 4 )-(η 5 -C 5 H 3 {CMe 2 CH 2 CH 2 CH=CH 2 })}Cl 2 ] (6) was obtained from the reaction of the lithium precursor [Li 2 (Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 3 {CMe 2 CH 2 CH 2 CH=CH 2 })}] (3) with zirconium tetrachloride. Catalytic hydrogenation of 4-6 gave the zirconocene complexes [Zr(η 5 -C 5 H 5 )(η 5 -C 5 H 4 (CMe 2 CH 2 -CH 2 CH 2 CH 3 )}Cl 2 ) (7), [Zr{η 5 -C 5 H 4 (CMe 2 CH 2 CH 2 CH 2 -CH 3 )) 2 Cl 2 ) (8) and [Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 3 {CMe 2 CH 2 -CH 2 CH 2 CH 3 })}Cl 2 ] (9), respectively. Hydroboration of 4-6 with 9-BBN (9-borabicyclo[3.3.1]nonane) yielded [Zr(η 5 -C5H5){η 5 -C 5 H 4 (CMe 2 CH 2 CH 2 CH 2 CH 2 BC 8 H 14 )}Cl 2 ] (10), [Zr{η 5 -C 5 H 4 (CMe 2 CH 2 CH 2 CH 2 CH 2 BC 8 H 14 )} 2 Cl 2 ) (11) and [Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 3 {CMe 2 CH 2 CH 2 CH 2 CH 2 BC 8 -H 14 })}Cl 2 ] (12), respectively, and the catalytic hydrosilylation of 4-6 with SiHMe 2 Cl gave [Zr(η 5 -C 5 H 5 )(η 5 -C 5 H 4 (CMe 2 -CH 2 CH 2 CH 2 CH 2 SiMe 2 Cl)}Cl 2 ] (13), [Zr{η 5 -C 5 H 4 (CMe 2 -CH 2 CH 2 CH 2 CH 2 SiMe 2 Cl)} 2 Cl 2 ] (14) and [Zr{Me 2 Si(η 5 -C 5 Me 4 )(η 5 -C 5 H 3 {CMe 2 CH 2 CH 2 CH 2 CH 2 SiMe 2 Cl})}Cl 2 ] (15), respectively. The dinuclear complex [Cl 2 Zr{Me 2 Si(η 5 -C 5 -Me 4 )(η 5 -C 5 H 3 {CMe 2 (CH 2 ) 4 SiMe 2 OSiMe 2 (CH 2 ) 4 Me 2 C}η 5 -C 5 -H 3 )(η 5 -C 5 Me 4 )SiMe 2 )ZrCl 2 ] (16) was obtained upon controlled hydrolysis of 15. The zirconocene compounds were tested as catalysts in the polymerisation of ethylene and propylene. Isotactic polypropylene with [mmmm] pentads of the order of 75 % were obtained with the ansa-zirconocene catalysts, whereas the unbridged metallocene catalysts produced atactic polypropylene. The molecular structures of 4 and 5 were determined by single-crystal X-ray diffraction studies.

ansa -Zirconocene complexes have been studied by Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR). Using the comparative molecular field analysis (CoMFA) method, the experimental results obtained for catalytic activity and polymer molecular weight have been successfully correlated with the steric and electrostatic 3D structural descriptors, which were calculated by density functional theory (DFT) methods.