Green synthesis of 1,3,5-triazines with applications in supramolecular chemistry and materials chemistry
A. Sánchez-Migallón, A. de la Hoz
Targets in Heterocyclic Systems 2017, 20, 140,175.
The 1,3,5-triazine ring is an extraordinary fragment that can take part in most types of intermolecular bonds. Microwave irradiation provides an efficient and green procedure for the selective preparation of s-triazines. Symmetrical and unsymmetrical 1,3,5-triazines have been obtained in good to excellent yields in short reaction times and under solvent free conditions. The structures have been determined by NMR-spectroscopy and X-ray crystallography. The optoelectronic and electrochemical properties have been investigated. The formation of complexes with Pd(II) and Ag(I), as well as the molecular recognition of glutarimide and riboflavin, demonstrate the extraordinary applications of these compounds.
Á. Cantín, M. V. Gomez, A. de la Hoz
Beilstein J. Org. Chem. 2016, 12, 2181–2188
Diels–Alder cycloaddition between cyclopentadiene and p-benzoquinone has been studied in the confined space of a pure silica zeolite Beta and the impact on reaction rate due to the concentration effect within the pore and diffusion limitations are discussed. Introduction of Lewis or Brønsted acid sites on the walls of the zeolite strongly increases the reaction rate. However, contrary to what occurs with mesoporous molecular sieves (MCM-41), Beta zeolite does not catalyse the retro-Diels–Alder reaction, resulting in a highly selective catalyst for the cycloaddition reaction.
A. M. Rodriguez, P. Prieto
New insights in the mechanism of the microwave-assisted PausoneKhand reaction
Tetrahedron 72 (2016) 7443-7448
A complete analysis of the stereoselectivity observed in the PausoneKhand reaction has been performed using computational calculations. The differences observed in the stereoselectivity when this reaction is performed either by conventional means or under microwave conditions have also been studied. The mechanisms suggested by MagnuseSchore and by Gimbert were used as a model in this investigation. The outcomes show that the observed diastereoselectivity is consistent with the mechanism proposed by Gimbert et al. Moreover, the high activation energy of the process could be responsible for the observed improvement under microwave irradiation.
A. de la Hoz, A. Díaz-Ortiz, P. Prieto
Alternative Energy Sources for Green Chemistry. Chapter 1. pp. 1-33
RSC Green Chemistry No. 47.
G. Stefanidis, A. Stankiewicz Eds.
Royal Society of Chemistry. ISBN: 9781782621409
Since the first publications on the use of microwave irradiation in synthetic chemistry, it was clear that this methodology would have a marked influence in all areas of this discipline. Reduction of reaction times, improved yields, modifications of selectivities, increased product purities and simplification of work-up procedures were described and, in most cases, these conditions and results could not be achieved by classical heating. This methodology can be included within the concept of Green Chemistry because the strong absorption of microwave irradiation by one component of the reaction would lead to shorter reaction times and improved energy efficiency. Moreover, the synergy with solvent-free conditions, solid catalysts and green solvents has expanded the green applications of this non-conventional energy source. Finally, the use of flow systems, another green methodology, has permitted the scale-up of microwave-assisted reactions under green conditions.
M. I. Lucío, F. Pichler, J. R. Ramírez, A. de la Hoz, A. Sánchez-Migallón, C. Hadad, M. Quintana, A. Giulani, M. V. Bracamonte, J. L. G. Fierro, C. Tavagnacco, M. A. Herrero, M. Prato, E. Vázquez
Chem. Eur.J.2016, 22,8879 –8888
The synthesis of functionalised carbon nanotubes as receptors for riboflavin (RBF) is reported. Carbon nanotubes, both single-walled and multi-walled, have been functionalised with 1,3,5-triazines and p-tolyl chains by aryl radical addition under microwave irradiation and the derivatives have been fully characterised by using a range of techniques. The interactions between riboflavin and the hybrids were analysed by using fluorescence and UV/Vis spectroscopic techniques. The results show that the attached functional groups minimise the π-π stacking interactions between riboflavin and the nanotube walls. Comparison of p-tolyl groups with the triazine groups shows that the latter have stronger interactions with riboflavin because of the presence of hydrogen bonds. Moreover, the triazine derivatives follow the Stern–Volmer relationship and show a high association constant with riboflavin. In this way, artificial receptors in catalytic processes could be designed through specific control of the interaction between functionalised carbon nanotubes and riboflavin.
F. León, P. Elizalde, P. Prieto, A. Sánchez-Migallón, A. M. Rodríguez, A. de la Hoz.
D. R. Corrochano, A. de la Hoz, A. M. Sánchez-Migallón,, R. Caballero, J. R. Ramírez
J. Clean. Prod. 2016, 118, 223-226.
The design of new systems with Donor–Acceptor properties is of great interest for the construction of optoelectronic new devices. Considering the strong supramolecular interaction of triazines with graphene a series of imine-derived triazines with Donor–Acceptor properties have been designed. These compounds have been prepared in good to excellent yields (47–92%) using Green conditions, i.e. microwave irradiation in the absence of an acid catalyst. Their properties as Donor–Acceptor systems have been studied by Ultraviolet–visible and fluorescence spectroscopy and by electrochemical studies. These imine derived triazines are blue-violet emitters (ca. 396 nm) and show large Stokes shifts (c.a. 6700 cm−1) and the electrochemical studies shows a high degree of communication between the acceptor triazines and the donor moieties (oxidation potentials up to 1.10 V). These characteristics makes them excellent candidates for the interaction with graphene and the construction of optoelectronic devices, as blue Light Emitting-Diodes (LEDs).
Chem. Eur.J. 2016, 144–152
The stereoselective synthesis of 1,3-diaminotruxillic acid derivatives has been achieved in high yields and short reaction times. The procedure starts from simple 5(4H)- oxazolones and is based on an efficient combination of CH orthopalladation, [2+2]-photocycloaddition on continuous flow microreactors using visible light from LED sources, and hydrogenation to selectively afford the epsilon isomer. More information can be found in the Full Paper by E. P. Urriolabeitia, M. V. Gómez, C. Cativiela et al. on page 144 ff.
Elena Serrano, Alberto Juan, Angel Garcia-Montero, Tatiana Soler, Francisco Jimenez-Marquez, Carlos Cativiela, M. Victoria Gomez, Esteban Urriolabeitia
Chem. Eur.J.2016, 22,144 –152
The stereoselective synthesis of ε-isomers of dimethyl esters of 1,3-diaminotruxillic acid in three steps is reported. The first step is the ortho-palladation of (Z)-2-aryl-4-aryliden-5(4H)-oxazolones 1 to give dinuclear complexes 2 with bridging carboxylates. The reaction occurs through regioselective activation of the ortho-CH bond of the 4-arylidene ring in carboxylic acids. The second step is the [2+2]-photocycloaddition of the CC exocyclic bonds of the oxazolone skeleton in 2 to afford the corresponding dinuclear ortho-palladated cyclobutanes 3. This key step was performed very efficiently by using LED light sources with different wavelengths (465, 525 or 625 nm) in flow microreactors. The final step involved the depalladation of 3 by hydrogenation in methanol to afford the ε-1,3-diaminotruxillic acid derivatives as single isomers
J. R. Ramírez, A. Ruiz-Carretero, M. Herrero. A. Sánchez-Migallón, A. de la Hoz
Dyes Pigments, 2016, 124, 203-209.
A new series of luminescent blue emissive bistriazines is described. Bistriazines with a naphthalene spacer were prepared using a green methodology that involved microwave irradiation, solvent free conditions and a reaction time of only 10 min. The synthesis was followed by a simple purification procedure. D-σ-A-σ-π-σ-A-σ-D systems were constructed using 1,5-naphthylidene as a planar π-bridge and different donor substituents were attached to the triazine ring. UV–vis and fluorescence spectroscopy showed that the increased conjugation in bistriazines with respect to monotriazines resulted in a 40-fold increase in the photoluminescence quantum yield (ΦF). The bistriazines were efficient blue emitters with ΦF values up to 0.87. The aggregation behavior and the optical and thermal properties of these systems have been studied. The bistriazines showed good thermal stability in conjunction with high ΦF values and they are therefore very promising materials for use in optoelectronic devices
In Environment, Energy and Climate change I: Environmental Chemistry of Pollutants and Wastes. The Handbook of Environmental Chemistry. Vol. 32. Pp. 405-428. Springer. 2015. ISBN: 978-3-319-12906-8
A. de la Hoz, A. Díaz-Ortiz, P. Prieto
C. Cebrián, J. de M. Muñoz, C. A. Strassert, P. Prieto, A. Díaz-Ortiz, A. de la Hoz
ChemPlusChem, 2015, 79, 1489-1497
A sustainable synthesis of alkenyl-1H-1,2,4-triazoles through the Hiyama reaction is reported, which employs water as solvent and sodium hydroxide to activate the silyl group under microwave irradiation, thereby leading to high product yields (51–93 %) in very short reaction times. Two substitution patterns were attained owing to the different reactivity of the third and fifth positions of the 1H-1,2,4-triazole unit, as evidenced by calculated condensed Fukui functions. Moreover, all compounds are good blue emitters (ΦF up to 0.69) in THF solution, although they exhibit an optical behavior dependent on the substitution. Excited-state theoretical investigations by the configuration interaction singles method and time-dependent density functional theory were performed not only to support and elucidate the studied photophysical properties, but also to create a predictive model to reduce the cost and optimize the search for new blue emitters based on this class of alkenyl-1H-1,2,4-triazoles.
A. García-Rodríguez, A. M. Rodríguez, P. Prieto, R. Andreu, S. Merino, J. Rodríguez-López
Eur. J. Org. Chem., 2015, 2394-2404
Bithiophene-based cruciforms with different stilbenoid arms at the 3,3′- and 5,5′-positions have been synthesized by various combinations of Suzuki and Horner–Wadsworth–Emmons (HWE) reactions. According to DFT calculations, the steric hindrance between the arms at the 3,3′-positions produces a twist angle of 57.6° between the two thiophene rings that form the 2,2′-bithiophene unit, an arrangement that leads to a swivel-cruciform structure. The UV/Vis spectra contained strong absorption bands at wavelengths consistent with a twisted molecule with little interaction between the arms. The ability of these compounds to form highly stable radical cations was demonstrated by cyclic voltammetry and this, together with their good solubility in organic solvents, indicates that these materials have potential for the development of solution-processed electronic devices.
M. J. Pastor, I. Torres, C. Cebrián, J. R. Carrillo, A. Díaz-Ortiz, E. Matesanz, J. Buendía, F. García, J. Barberá, P. Prieto, L. Sánchez
Chem. Eur. J., 2015, 21, 1795-1802.
The synthesis of a series of 4-aryl-3,5-bis(arylethynyl)aryl-4H-1,2,4-triazoles derivatives is reported and the influence exerted by peripheral substitution on the morphology of the aggregates generated from these 1,2,4-triazoles is investigated by SEM imaging. The presence of paraffinic side chains results in long fibrillar supramolecular structures, but unsubstituted triazoles self-assemble into thinner ribbons and needle-like aggregates. The crystals obtained from methoxy-substituted triazoles have been utilised to elaborate a model that helps to justify aggregation of the investigated 1,2,4-triazoles, in which the operation of arrays of CH⋅⋅⋅π non-covalent interactions plays a significant role. The results presented herein demonstrate the ability of simple molecules to behave as multitasking scaffolds with different properties, depending on peripheral substitution. Thus, although 1,2,4-triazoles without long paraffinic side chains exhibit optical waveguiding behaviour, triazoles endowed with peripheral paraffinic side chains exhibit hexagonal columnar mesomorphism.
A. M. Rodríguez, P. Prieto, A. de la Hoz, A. Díaz-Ortiz, J. I. García.
ChemistryOpen, 2015, 4, 308-317
The aim of this work was to determine the parameters that have decisive roles in microwave-assisted reactions and to develop a model, using computational chemistry, to predict a priori the type of reactions that can be improved under microwaves. For this purpose, a computational study was carried out on a variety of reactions, which have been reported to be improved under microwave irradiation. This comprises six types of reactions. The outcomes obtained in this study indicate that the most influential parameters are activation energy, enthalpy, and the polarity of all the species that participate. In addition to this, in most cases, slower reacting systems observe a much greater improvement under microwave irradiation. Furthermore, for these reactions, the presence of a polar component in the reaction (solvent, reagent, susceptor, etc.) is necessary for strong coupling with the electromagnetic radiation. We also quantified that an activation energy of 20–30 kcal mol−1 and a polarity (μ) between 7–20 D of the species involved in the process is required to obtain significant improvements under microwave irradiation
A.M. Rodríguez, A. de la Hoz, F. Jiménez-Márquez, R.M. Fratila, P.A. Berneveld, V. Gómez-Almagro, A. Velders
Analytical Chem. 2015, 87, 10547-10555.
Conventional methods to determine the kinetic parameters for a certain reaction require multiple, separate isothermal experiments, resulting in time- and material-consuming processes. Here, an approach to determine the kinetic information within a single nonisothermal on-flow experiment is presented, consuming less than 10 μmol of reagents and having a total measuring time of typically 10 min. This approach makes use of a microfluidic NMR chip hyphenated to a continuous-flow microreactor and is based on the capabilities of the NMR chip to analyze subnanomole quantities of material in the 25 nL detection volume. Importantly, useful data are acquired from the microreactor platform in specific isothermal and nonisothermal frames. A model fitting the experimental data enables rapid determination of kinetic parameters, as demonstrated for a library of isoxazole and pyrazole derivatives.
J. R. Ramírez, R. Caballero, J. Guerra, A. Ruiz-Carretero, A. Sánchez-Migallón, A. de la Hoz
ACS Sustainable Chem. Eng., 2015, 3 (12), pp 3405–3411
The green synthesis of asymmetric star-shaped 2,5-dimethoxyphenylamino-1,3,5-triazine derivatives using microwave irradiation in the absence of solvent is described. The title compounds have been characterized, and their properties as donor–acceptor (D–A) systems have been studied by UV–vis, fluorescence spectroscopy and electrochemical studies. The formation of excimers and the aggregation of these star-shaped triazine systems have been demonstrated.
A. Díaz-Ortiz, P. Prieto, J. R. Carrillo, R. Martín, I. Torres.
Curr. Org. Chem. 2015, 19, 568-584
The 1,2,4-triazole system has shown excellent electron-transport and hole-blocking properties owing to its highly electron-deficient nature. Accordingly, a large number of 1,2,4-triazole derivatives have been described as having a wide variety of uses in materials science. Triazoles are widely used in transition-metal complexes or metal-organic frameworks (MOFs), but metal-free 1,2,4-triazole derivatives have also exhibited interesting and useful properties as materials. The use of these derivatives, either as small molecules or polymers, in light-emitting devices has allowed the fabrication of OLEDs, PHOLEDs and PLEDs with excellent properties. Other materials have exhibited liquid crystalline or optical waveguide behavior or have found applications in PEMFCs, organic photovoltaic cells and data storage devices. The aim of this review is to discuss the most important metal-free derivatives bearing 1,2,4- triazole moieties with applications as organic materials.
R. Fratila, M. V. Gómez, S. Sykora, A. Velders.
Nature Commun., 2014, 5, art. 3025
Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique, but its low sensitivity and highly sophisticated, costly, equipment severely constrain more widespread applications. Here we show that a non-resonant planar transceiver microcoil integrated in a microfluidic chip (detection volume 25 nl) can detect different nuclides in the full broad-band range of Larmor frequencies (at 9.4 T from 61 to 400 MHz). Routine one-dimensional (1D) and two-dimensional (2D), homo- and heteronuclear experiments can be carried out using the broad-band coil set-up. Noteworthy, heteronuclear 2D experiments can be performed in a straightforward manner on virtually any combination of nuclides (from classical 1H–13C to more exotic combinations like 19F–31P) both in coupled and decoupled mode. Importantly, the concept of a non-resonant system provides magnetic field-independent NMR probes; moreover, the small-volume alleviates problems related to field inhomogeneity, making the broad-band coil an attractive option for, for example, portable and table-top NMR systems.
M. Durán-Prado, J. Frontiñán, R. Santiago-Mora, J. R. Peinado, C. Parrado-Fernández, M. V. Gómez, M. Moreno, J. A. López-Domínguez, J. M. Villalba, F. J. Alcaín.
PLoS One, 2014, 9 – 11, e109223
Neuropathological symptoms of Alzheimer’s disease appear in advances stages, once neuronal damage arises. Nevertheless, recent studies demonstrate that in early asymptomatic stages, ß-amyloid peptide damages the cerebral microvasculature through mechanisms that involve an increase in reactive oxygen species and calcium, which induces necrosis and apoptosis of endothelial cells, leading to cerebrovascular dysfunction. The goal of our work is to study the potential preventive effect of the lipophilic antioxidant coenzyme Q (CoQ) against ß-amyloid-induced damage on human endothelial cells. We analyzed the protective effect of CoQ against Aβ-induced injury in human umbilical vein endothelial cells (HUVECs) using fluorescence and confocal microscopy, biochemical techniques and RMN-based metabolomics. Our results show that CoQ pretreatment of HUVECs delayed Aβ incorporation into the plasma membrane and mitochondria. Moreover, CoQ reduced the influx of extracellular Ca2+, and Ca2+ release from mitochondria due to opening the mitochondrial transition pore after β-amyloid administration, in addition to decreasing O2.− and H2O2 levels. Pretreatment with CoQ also prevented ß-amyloid-induced HUVECs necrosis and apoptosis, restored their ability to proliferate, migrate and form tube-like structures in vitro, which is mirrored by a restoration of the cell metabolic profile to control levels. CoQ protected endothelial cells from Aβ-induced injury at physiological concentrations in human plasma after oral CoQ supplementation and thus could be a promising molecule to protect endothelial cells against amyloid angiopathy.
A. Ruiz, C. A. Mardones, C. Vergara, D. von Baer, S. Gómez Alonso, M. V. Gómez, I. Hermosín
J. Agr. Food Chem., 2014, 62, 6918-6925.
Calafate (Berberis microphylla G. Forst) is an edible wild berry growing in South Patagonia that is very rich in anthocyanins and hydroxycinnamic acid derivatives. Calafate contains unusual phenolic compounds compared to other berries, such as anthocyanidin dihexosides, different from the common 3,5-diglucosides, and isomeric esters of caffeic acid with hexaric acids. After isolation, their structures have been elucidated by UV–vis, MS/MS, and NMR spectroscopies. The anthocyanidin dihexosides constitute the complete series of 3,7-β-O-diglucosides of the five anthocyanidins usually found in calafate, the structures of which were completely elucidated in the cases of delphinidin, petunidin, and malvidin derivatives and tentatively suggested in the cases of cyanidin and peonidin, and their occurrence seems to be characteristic of calafate among other wild berries from South Patagonia. With regard to caffeoyl-hexaric acids, two of four isomers have been assigned as 3- and 4-trans-caffeoyl-glucaric acids, but the determination of the linkage position for each isomer was not possible. A third isomer was also isolated, but it easily degraded and was suggested to be the 2- or 5-trans-caffeoyl-glucaric acid. The caffeoyl-glucaric acids account for around half of the pool of hydroxycinnamic acid derivatives in calafate.
A. de la Hoz, A. Sánchez-Migallón, B. T. Pelado, J. R. Ramírez
Arkivoc, 2014, ii, 308-318.
An efficient and green synthesis of 2,4-dimethoxybenzyaminotriazines is described, by reaction of disubstituted triazines with 2,4-dimethoxybenzylamine under microwave irradiation and in solvent-free conditions. NMR spectroscopy has been used to determine the free energy of activation of the restricted rotation of the ArylN-triazine bond that is a slow process at room temperature. Contrarily, the benzylN-triazine bond shows a rapid rotation at room temperature.
B. Egle, J. de M. Muñoz, J. Alcázar, W. de Borggraeve, A. de la Hoz, A. Díaz-Ortiz
J. Flow Chem., 2014, 4, 22-25
The first example of an alkyl–aryl Negishi coupling in a practical, sustainable, and high-yielding process using a silica-supported catalyst in flow is described. Excellent conversions and good functional group compatibility were obtained under very mild conditions. Functionalized alkyl groups were also introduced to provide access to synthetically useful molecules and to demonstrate the versatility of the method. The scalability was assessed, and a throughput of 7.5 mmol/h of processed substrate was achieved. All crude products were free from phosphine derivatives and ready for use in subsequent reaction steps.
A. Ruiz-Carretero, J. R. Ramírez, A. Sánchez-Migallón, A. de la Hoz
Microwave-Assisted Selective and Efficient Synthesis of 1,3,5-Triazinyl Mono and Bisureas
Tetrahedron, 2014, 70, 1733-1739.
An efficient and sustainable microwave-assisted approach for the one-step preparation of a wide range of 1,3,5-triazinyl mono- and bisureas has been developed, combining solvent-free conditions and microwave irradiation. In these conditions the very unreactive amino groups of 1,3,5-triazine-2,4-diamines successfully react with phenylisocyanate to yield selectively mono and bisureas.
This protocol resulted in the shortest reaction times reported so far and is generally applicable for the
preparation of these valuable heterocyclic systems.
A. M. Rodríguez, P. Prieto, A. de la Hoz, A. Díaz-Ortiz, J. I. García.
Org. Biomol. Chem., 2014, 12, 2436-2445.
A DFT computational mechanistic study of the ring closing metathesis (RCM) reaction of diallyl ether or N,N-diallyl-p-toluenesulfonamide catalyzed by a second generation Grubbs-type ruthenium carbene complex has been carried out. This study was performed at the PCM(CH2Cl2)-B3LYP/6-311+G(2d,p)//B3LYP/SDD theory level. The aim of this work was to shed light on the influence that microwave irradiation has on these reactions and to gain insight into the so-called ‘molecular radiator’ effect. The outcomes obtained indicate that thermal effects induced by microwave irradiation decrease the catalytic induction period. The presence of a polar reagent and/or polar species in the reaction that increases the polarity of the medium may enhance this thermal effect.
N. Alonso, J. de M. Muñoz, B. Egle, J. L. Vrijdag, W. de Borggraeve, A. de la Hoz, A. Díaz-Ortiz, J. Alcázar
J. Flow Chem., 2014, 4, 105-109
The first continuous flow carbonylation reaction using aryl formates as CO precursor is reported. The reaction is practical, scalable and high yielding. The use of a flow protocol safely allows expanding the scope to activated chlorides, nitrogen heterocycles and to the selective introduction of an ester group in dihalo-derivatives. Further selective reduction of the ester formed to an aldehyde in flow is also described.
A. Ruiz-Carretero, O. Noguez, T. Herrera, J. R. Ramírez, A. Sánchez-Migallón, A. de la Hoz.
J. Org. Chem., 2014, 79, 4909-4919.
A series of mono- and bistriazine derivatives were selectively prepared in high yields using microwave irradiation. Donor substituents were attached on the triazine ring, including pyrazolyl-substituted anilines and o-, m-, and p-phenylenediamine as π-conjugated spacers. This method was used to build σ–π–σ–A−σ–D systems for monotriazines and D−σ–A−σ–π–σ–A−σ–D systems for bistriazines. A study of the optoelectronic properties was performed by UV–vis and fluorescence spectroscopy and cyclic voltammetry. The monotriazines do not show any emission, but the bistriazines are blue emitters and show an interesting solvatochromic effect with large Stokes shifts of more than 10 000 cm–1 in some cases and quantum yields up to 23%. The optoelectronic properties depend on the conjugation and the position and donor character of the substituents and spacers. Cyclic voltammetry was used to determine the energy levels (HOMO and LUMO) in the bistriazines. An increase in the energy of the HOMO and a decrease in the energy of the LUMO were observed upon extending the conjugation. The title compounds showed interesting properties for use in optoelectronic devices, especially as blue emitters.
D. Cáceres, C. Cebrián, A. M. Rodríguez, J. R. Carrillo, A. Díaz-Ortiz, P. Prieto, F. Aparicio, F. García, L. Sánchez
Ribbon-like supramolecular structures prepared by the organized aggregation of 4-aryl-4H-1,2,4-triazoles act as optical waveguides that propagate photoluminescence
Chem. Commun., 2013, 49, 621-623
Substitution Reactions in Green Chemistry
A. de la Hoz, A. Díaz-Ortiz
Oxford Handbook of Green Chemistry: From Philosophy to Industrial Applications. Oxford University Press. ISBN: 978-0-195-37355-4. In the press
A. Nunes, C. Bussy, L. Gherardini, M. Meneghetti, M. A. Herrero, A. Bianco, M. Prato, T. Pizzorusso, K. T Al-Jamal, and K. Kostarelos
Carbon nanotubes (CNTs) are increasingly being utilized in neurological applications as components of implants, electrodes or as delivery vehicles. Any application that involves implantation or injection of CNTs into the CNS needs to address the distribution and fate of the material following interaction and residence within the neuronal tissue. Here we report a preliminary study investigating the fate and structural integrity of amino-functionalized CNTs following stereotactic administration in the brain cortex. Materials & methods: The CNTs investigated had previously shown the capacity to internalize in various cell types of the CNS. An aqueous suspension of multiwalled CNT-NH3 + was stereotactically injected into the mouse brain cortex. Their interaction with neural cells and consequent effects on the CNT structural integrity was investigated by optical, transmission electron microscopy and Raman spectroscopy of brain tissue sections for a period between 2 and 14 days post cortical administration. Results & discussion: The occurrence of severe nanotube structure deformation leading to partial degradation of the chemically functionalized-multiwalled CNT-NH3 + in vivo following internalization within microglia was revealed even at early time points. Such initial observations of CNT degradation within the brain tissue render further systematic investigations using high-resolution tools imperative.
Nanomedicine, 2012, 7, 1485-1494.
K. T. Al-Jamal, A. Nunes, L. Methven, H. Ali-Boucetta, S. Li, F. M. Toma, M. A. Herrero, W. T. Al-Jamal, H. M. M. ten Eikelder, J. Foster, S. Mather, M. Prato, A. Bianco, K. Kostarelos
Angew. Chem., 2012, 124, 6495-6499.
M. Quintana, E. Vázquez, M. Prato
Graphene is considered a promising material for a range of new applications from flexible electronics to functional nanodevices, such as biosensors or intelligent coatings. Therefore researchers need to develop protocols for the mass production of graphene. One possible method is the exfoliation of graphite to form stable dispersions in organic solvents or even water. In addition, researchers need to find effective ways to control defects and locally induced chemical changes. We expect that traditional organic chemistry can provide solutions to many of these challenges. In this Account, we describe our efforts toward the production of stable dispersions of graphene in a variety of solvents at relatively high concentrations and summarize representative examples of the organic reactions that we have carried out using these stable dispersions.
The sonication procedures used to solubilize graphene can often damage these materials. To mitigate these effects, we developed a new methodology that uses mechanochemical activation by ball-milling to exfoliate graphite through interactions with melamine (2,4,6-triamine-1,3,5-triazine) under solid conditions. Alternatively, the addition of reducing agents during sonication leads to larger graphene layers in DMF. Interestingly, the treatment with ferrocene aldehyde, used as a radical trap, induces the formation of multiwalled carbon nanotubes. The resulting graphene sheets, stabilized by the interactions with the solvent, are suitable materials for performing organic reactions.
Relatively few organic reactions have been performed in stable dispersions of graphene, but organic functionalization of these materials offers the opportunity to tune their properties. In addition, thermal treatments can remove the appended organic moieties, restoring the intrinsic properties of pristine graphene. We describe a few examples of organic functionalization reactions of graphene, including 1,3-dipolar cycloadditions, amide condensations, nitrene additions, and radical reactions. The design of novel protocols for further organic functionalization should increase our knowledge of the fundamental chemistry of graphene and spur the further development and application of these materials.
Acc. Chem. Res. , DOI: 10.1021/ar300138e (2012).
A. Montellano Lopez, F. Scarel, N. Rubio Carrero, E. Vázquez, A. Mateo-Alonso, T. Da Ros, M. Prato
The synthesis, characterization and DNA binding studies of a series of polycationic fullerene adducts are reported. These cationic species, exhibiting reasonably high water solubility and a heterogeneous distribution of positive charges, can efficiently complex plasmid DNA. Electrophoresis studies show different DNA binding efficiencies for different adducts, some of which can be considered excellent candidates for DNA binding therapies
Org. Lett. 2012, 14, 4450-4453
F. C. Pérez-Martínez, B. Carrión, M. I. Lucio , N. Rubio, M. A. Herrero, E. Vázquez, V. Ceña
We synthesized a non-viral delivery system (f-CNH3) for small interfering RNA (siRNA) by anchoring a fourth-generation polyamidoamine dendrimer (G4-PAMAM) to carbon nanohorns (CNHs). Using this new compound, we delivered a specific siRNA designed to knockdown cofilin-1, a key protein in the regulation of cellular cytoskeleton, to human prostate cancer (PCa) cells. The carbon nanohorn (CNH) derivative was able to bind siRNA and release it in the presence of an excess of the polyanion heparin. Moreover, this hybrid nanomaterial protected the siRNA from RNAse-mediated degradation. Synthetic siRNA delivered to PCa cells by f-CNH3 decreased the cofilin-1 mRNA and protein levels to about 20% of control values. Docetaxel, the drug of choice for the treatment of PCa, produced a concentration-dependent activation of caspase-3, an increase in cell death assessed by lactate dehydrogenase release to the culture medium, cell cycle arrest and inhibition of tumor cell proliferation. All of these toxic effects were potentiated when cofilin-1 was down regulated in these cells by a siRNA delivered by the nanoparticle. This suggests that knocking down certain proteins involved in cancer cell survival and/or proliferation may potentiate the cytotoxic actions of anticancer drugs and it might be a new therapeutic approach to treat tumors.
Biomaterials, 2012, 33, 8152-8159.
Carbon nanohorns functionalized with polyamidoamine dendrimers as efficient biocarrier materials for gene therapy
J. Guerra, M. A. Herrero, B. Carrión, F. C. Pérez-Martínez , M. Lucio, N. Rubio , M. Meneghetti , M. Prato , V. Ceña, E. Vázquez
Carbon nanohorns are suitable platforms for use in biological applications. Their high surface areas allow the incorporation of molecular entities, such as polyamidoamine dendrimers. In this work, we report the synthesis, structural characterization and biological data of new hybrid systems of carbon nanohorns that hold polyamidoamine dendrimers. One of these derivatives has been employed as an agent for gene delivery. The system is able to release interfering genetic material diminishing the levels of a house-keeping protein and a protein directly involved in prostate cancer development. Importantly, this hybrid material is also far less toxic than the corresponding free dendrimer. These results allow us to conclude that these nanomaterials can be exploited as useful non-viral agents for gene therapy.
Carbon, 2012, 50, 2832–2844.
J. M. Muñoz, J. Alcázar, A. de la Hoz, A. Díaz-Ortiz. A mild, clean, practical, sustainable and high yielding procedure for Suzuki–Miyaura cross-coupling in a single pass using a silica-supported palladium catalyst is described. The catalyst can be used in more than 30 reactions and for more than 8 hours of continuous processing without a decrease in reactivity due to the low leaching observed. Different halides/pseudo halides and organoboron compounds can be used without modifying the standard procedure.
Adv. Synth. Catal. 2012, 18, 3456-3460.
Flow Microwave Technology and Microreactors in Synthesis
I. R. Baxendale, C. Hornung, S. V. Ley, J. M. Muñoz, A. Wikström. A bespoke microwave reactor with a glass containment cell has been developed for performing continuous flow reactions under microwave heating. The prototype unit has been evaluated using a series of standard organic chemical transformations enabling scale-up of these chemical processes. As part of the development, a carbon-doped PTFE reactor insert was utilized to allow the heating of poorly absorbing reaction media, increasing the range of solvents and scope of reactions that can be performed in the device.
Aust. J. Chem. http://dx.doi.org/10.1071/CH12365
M. Moreno , M. V. Gómez , C. Cebrián , P. Prieto, A. de la Hoz, A. Moreno. Microwave-assisted organic synthesis and continuous-flow techniques have been successfully employed for the preparation of conjugated linoleic acids (CLA), compounds with high health beneficial effects. A good production rate of CLA was obtained. A sustainable methodology for the differentiation of both positional and geometrical CLA isomers (diene), based on the analysis by NMR spectroscopy of the resulting Diels–Alder cycloadducts with an appropriate dienophile, was developed.
Microwaves in Organic Synthesis. Third Edition. A. de la Hoz, A. Loupy. Editores. Wiley (Weinheim) ISBN 3-527-33116-6 (in press).
Selectivity under the action of microwave irradiation. In Microwaves in Organic Synthesis. Third Edition. A. de la Hoz, A. Díaz-Ortiz, J.R. Carrillo, M.A. Herrero. Eds. A. de la Hoz, A. Loupy Wiley (Weinheim) ISBN 3-527-33116-6 (in press).
Elucidation of microwave effects: Methods, theories and predictive models. In Microwaves in Organic Synthesis. Third Edition. A. de la Hoz, A. Díaz-Ortiz, A. Sánchez Migallón, M.V. Gómez Almagro, P. Prieto. Eds. A. de la Hoz, A. Loupy. Wiley (Weinheim) ISBN 3-527-33116-6 (in press).
J. M. Muñoz, J. Alcázar, A. Diaz-Ortiz; A. de la Hoz. The reduction of esters to aldehydes is an important transformation in organic chemistry and several reducing agents have been described. However, the use of this reaction in medicinal and natural product chemistry is limited due to the instability of the intermediates and the high reactivity of the reaction products. In the current article, the general and selective reduction of esters with diisobutyl-tert-butoxyaluminum hydride in flow is reported. This reagent allows esters to be reduced in the presence of different functional groups, including those considered to be of similar or higher reactivity.
Eur. J. Org. Chem. 2012, 260-263.
L. Lacerda, J. Russier, G. Pastorin, M.A. Herrero, E. Venturelli, H. Dumortier, K. Al-Jamal, M. Prato, K. Kostarelos. Understanding the mechanisms responsible for carbon nanotube (CNT) internalisation into live cells is considered critical both from a fundamental point of view and for further engineering of CNT-based delivery systems to intracellular targets. While several studies are focused on the development of such CNT-based delivery systems, attempts to systematically elucidate the cellular uptake mechanisms of CNTs are still rather limited. The aim of the present study is to evaluate the cellular internalisation of chemically functionalised multi-walled carbon nanotubes (f-MWCNTs) in the presence of different well-known cellular uptake inhibitors. Our data reveal how f-MWCNTs are able to translocate across cell membranes of both phagocytic and non-phagocytic cell lines. We have evidenced that at least 30–50% of f-MWCNTs are taken up by cells through an energy-independent mechanism. This characteristic makes nanotubes loaded with therapeutic or diagnostic cargos extremely interesting as the release of active molecules directly into the cytoplasm increase their biological activity and therapeutic efficacy.
Biomaterials 2012, 33, 3334-3343.
A.M. Rodriguez, C. Cebrián, P. Prieto, J. I. García, A. de la Hoz, Á. Díaz-Ortiz. A DFT computational mechanistic study of the [2+2+2] cyclotrimerization of a diyne with benzonitrile, catalyzed by a cobalt complex, has been carried out. Three alternative catalytic cycles have been examined together with the precatalytic step (responsible for the induction period). The favored mechanism takes place by means of an intramolecular metal-assisted [4+2] cycloaddition. The beneficial role of microwave activation has been studied. It is concluded that microwave irradiation can decrease the catalytic induction period through thermal effects and can also increase the triplet lifetime and promote the reaction, thus improving the final yield.
Chem. Eur. J. 2012, 18, 6217-6224
J.M. Muñoz, J. Alcázar, A. de la Hoz, A. Díaz-Ortíz, S.-A. Alonso de Diego. A safe, green and functional-group-tolerant flow version of the direct amide bond formation mediated by Grignard reagents (the Bodroux reaction) is described. The procedure can be applied to a wide variety of primary and secondary amines and anilines, as well as to aromatic and aliphatic esters. The flow approach leads to improved yields and selectivities in the reaction, which has a sustainable purification procedure and a simple scale-up. This reaction represents an efficient and green alternative to the use of alkylaluminium and metal-catalyzed procedures.
Green Chem. 2012, 14, 1335-1341.
A. M. Rodriguez, A. Juan, M. V. Gómez, A. Moreno, A. de la Hoz. An efficient method was developed for the synthesis of 3,4,5-trisubstituted and 3,5-disubstituted isoxazoles by using continuous-flow microwave-heated microreactors. A study on the separate effects of the temperature, continuous-flow regime, and microwave irradiation showed that the continuous-flow regime had important effects for less reactive diketones, where microwave heating enhanced the reaction, permitting the formation of 5-methyl-3-phenylisoxazole, which was not formed in the absence of microwaves.
Synthesis 2012, 44, 2527-2530
A M Rodriguez, P Prieto, A de la Hoz, A Díaz-Ortiz.
Computational calculations can be used as a predictive tool in Microwave-Assisted Organic Synthesis (MAOS). A DFT study on Intramolecular Diels-Alder reactions (IMDA) indicated that the activation energy of the reaction and the polarity of the stationary points are two fundamental parameters to determine “a priori” if a reaction can be improved by using microwave irradiation. –
Chiara Baldacchini, Maria Antonia Herrero Chamorro, Maurizio Prato, Salvatore Cannistraro. The integration of redox proteins with nanomaterials has attracted much interest in the past years, and metallic single-walled carbon nanotubes (SWNTs) have been introduced as efficient electrical wires to connect biomolecules to metal electrodes in advanced nano-biodevices. Besides preserving biofunctionality, the protein–nanotube connection should ensure appropriate molecular orientation, flexibility, and efficient, reproducible electrical conduction. In this respect, yeast cytochrome c redox proteins are connected to gold electrodes through lying-down functionalized metallic SWNTs. Immobilization of cytochromes to nanotubes is obtained via covalent bonding between the exposed protein thiols and maleimide-terminated functional chains attached to the carbon nanotubes. A single-molecule study performed by combining scanning probe nanoscopies ascertains that the protein topological properties are preserved upon binding and provides unprecedented current images of single proteins bound to carbon nanotubes that allow a detailed I–Vcharacterization. Collectively, the results point out that the use as linkers of suitably functionalized metallic SWNTs results in an electrical communication between redox proteins and gold electrodes more efficient and reproducible than for proteins directly connected with metal surfaces. – Advanced Functional Materials, 2011, 1, 153–157.
N. Rubio, C. Fabbro, M. A. Herrero, A. de la Hoz, M. Meneghetti, J. L. G. Fierro, M. Prato, E. Vázquez. Single-walled carbon nanotubes (SWNTs) can be successfully cut with relatively homogeneous sizes using a planetary mill. The optimized conditions produce highly dispersible SWNTs that can be efficiently functionalized in a variety of synthetic ways. As clearly shown by Raman spectroscopy, the milling/cutting procedure compares very favorably with the most common way of purifying SWNTs, namely, treatment with strong oxidizing acids. Moreover a similar milling process can be used to functionalize and cut pristine SWNTs by one-step nitrene chemistry.- Small, 2011, 7, 665-674.
Ángel Diaz-Ortiz, Antonio de la Hoz, Jesus R. Alcazar, Jose; A. Carrillo, Maria Herrero, Alberto Fontana, Juan de M. Munoz, Pilar Prieto, Abel de Cozar. Organic reactions performed in the absence of solvent in domestic ovens without appropriate temperature control are generally considered as not reproducible, particularly when different instruments are used. For this reason, reproducibility has historically been one of the major issues associated with Microwave-Assisted Organic Synthesis (MAOS) especially when domestic ovens are involved. The lack of reproducibility limits the general applicability and the scale up of these reactions. In this work several solvent-free reactions previously carried out in domestic ovens have been translated into a single-mode microwave reactor and then scaled up in a multimode oven. The results show that most of these reactions, although not considered as reproducible, can be easily updated and applied in microwave reactors using temperature-controlled conditions. Furthermore, computational calculations can assist to explain and/or predict whether a reaction will be reproducible or not. –
Combinatorial Chemistry & High Throughput Screening, 2011, 14, 2, 109-116.
M. Moreno, A. Moreno, M. V. Gómez, J. M. Poveda, L. Cabezas.
Magnetic Resonance in Food Science: An Exciting Future. 2011, 52, 54-59. RSC.
A. Moreno, L. F. Labrador, M. Moreno, M. S. Pérez, M. A. González, E. M. Sánchez-Palomo, J. M. Lemus.
Magnetic Resonance in Food Science: An Exciting Future. 2011, 52, 60-67. RSC.
C. Lucas-Torres, M. Moreno, A. Juan, A. de la Hoz, A. Moreno.
Magnetic Resonance in Food Science: An Exciting Future. 2011, 52, 100-104. RSC.
A. Casas, C. Lucas-Torres. A. Moreno, A. Pérez, M. J. Ramos, A. Simón.
Fuel, 2012, 92, 180-186
Valentín Hornillos, Javier Guerra, Abel de Cózar, Pilar Prieto, Sonia Merino, Miguel A. Maestro, Enrique Díez-Barra and Juan Tejeda. The syntheses of first generation dendritic compounds bearing 1,1′-alkane-1,1-diylbis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)palladium(II) dibromide on the periphery are described. The metallabiscarbene moieties have also been studied separately from the dendrimer. These compounds display a non-symmetric boat-to-boat conformational equilibrium that has axial and equatorial arrangements. The predominance of the axial conformer in the equilibrium is supported by DFT calculations. The X-ray solid state structures of axial conformers of 3-hydroxy- and 3-mesyloxy-1,1′-propane-1,1-diylbis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)palladium(II) dibromide are reported. These complexes display modest catalytic activity in the Heck reaction with activated aryl bromides and the dendritic catalysts were more active than the corresponding non-dendritic mononuclear species, a finding indicative of a cooperative effect.
Dalton Trans., 2011, 40, 4095-4103
J. Alcázar, A. de Cózar, A. de la Hoz, A. Díaz-Ortiz, J. R. Carrillo, M. A. Herrero, J. M. Muñoz, P. Prieto.
Microwave Heating ISBN 978-953-307-325-5. InTech. 2011, 137-162.
Substitution Reactions in Green Chemistry.
A. de la Hoz, A. Díaz-Ortiz. Handbook of Green Chemistry. Oxford University Press. in press.
J. de Mata Muñoz, J. Alcázar, A. Diaz-Ortiz; A. de la Hoz.
Reduction of nitriles to aldehydes with diisobutylaluminium hydride (DIBAL-H) is an important transformation in organic chemistry. But the use of this reaction is limited for the lack of reproducibility due to the instability of the intermediates formed. In the current article we disclose the improvement of the reaction applying continuous flow technology.
Tetrahedron Lett., 2011, 52, 6058-6060
V. León, M. Quintana, M. A. Herrero, J. L. G. Fierro, A. de la Hoz, M. Prato, E. Vázquez.
We report a simple, practical scalable procedure to produce few-layer graphene sheets using ball-milling. Commercially available melamine can be efficiently used to exfoliate graphite and generate concentrated water or DMF dispersions. Chem. Commun., 2011, 47, 10936-10938
F. Montilla, F. Huerta, D. Salinas-Torres, E. Morallón, C. Cebrián, P. Prieto, Á. Díaz-Ortiz, A. de la Hoz, J.R. Carrillo, C. Romero.
Novel electropolymerizable monomers based on triazole–thiophene units were characterized by both spectroscopic and electrochemical methods. It was found that those monomers which were enriched with additional thiophene units in their chemical structure showed red-shifted electronic transitions and lower oxidation potentials when compared with the short-chain disubstituted triazole monomer. The monomers studied were electropolymerized in organic medium giving rise to their corresponding electroactive polymers. These materials can be p-doped at potentials values which can be properly correlated with the thiophene conjugation length of the parent precursor. As a general rule, it was observed that the longer the conjugation length, the lower the HOMO level. Only the alternating bisthiophene–triazole polymer, poly-TTT, can be both p- and n-doped within the electrochemical window of the solvent employed. The doping processes are characterized by the formation of charge traps that avoid the reversible recovery of the injected charge. In addition, polaronic species formed upon electrochemical doping seem to be at the origin of the electronic transition bands observed for all the materials in the visible low-frequency to near-infrared optical range.
Electrochim. Acta. 2011, 58, 215-222.
C. Oelsner, M. A. Herrero, C. Ehli, M. Prato, D.M. Guldi
Electron-donating ferrocene units have been attached to SWNTs, with different degrees of functionalization. By means of a complementary series of novel spectroscopic techniques (i.e., steady-state and time-resolved), we have documented that mutual interactions between semiconducting SWNT and the covalently attached electron donor (i.e., ferrocene) lead, in the event of photoexcitation, to the formation of radical ion pairs. In the accordingly formed radical ion pairs, oxidation of ferrocene and reduction of SWNT were confirmed by spectroelectrochemistry. It is, however, shown that only a few semiconducting SWNTs [i.e., (9,4), (8,6), (8,7), and (9,7)] are susceptible to photoinduced electron transfer processes. These results are of relevant importance for the development of SWNT-based photovoltaics.
J. Am. Chem. Soc. 2011, 133, 18696–18706
Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing
Stroke is the second cause of death worldwide with ischemic stroke accounting for 80% of all stroke insults. Caspase-3 activation contributes to brain tissue loss and downstream biochemical events that lead to programmed cell death after traumatic brain injury. Alleviation of symptoms following ischemic neuronal injury can be potentially achieved by either genetic disruption or pharmacological inhibition of caspases. Here, we studied whether silencing of Caspase-3 using carbon nanotube-mediated in vivo RNA interference (RNAi) could offer a therapeutic opportunity against stroke. Effective delivery of siRNA directly to the CNS has been shown to normalize phenotypes in animal models of several neurological diseases. It is shown here that peri-lesional stereotactic administration of a Caspase-3 siRNA (siCas 3) delivered by functionalized carbon nanotubes (f-CNT) reduced neurodegeneration and promoted functional preservation before and after focal ischemic damage of the rodent motor cortex using an endothelin-1 induced stroke model. These observations illustrate the opportunity offered by carbon nanotube-mediated siRNA delivery and gene silencing of neuronal tissue applicable to a variety of different neuropathological conditions where intervention at well localized brain foci may offer therapeutic and functional benefits.
Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 10952-10957