Publications

2017

The organic chemistry of poly(1H-pyrazol-1-yl)methanes

I. Alkorta, R. M. Claramunt, E. Díez-Barra, J. Elguero, A. de la Hoz, C. López

Coordination Chemistry Reviews 339 (2017) 153–182

Since their first synthesis by Hückel (1937) and the first systematic exploration by Trofimenko (1970), interest in poly(1H-pyrazol-1-yl)methanes (bis, tris and tetrakis) has increased dramatically. This review focuses on the synthesis and reactivity of these ligands and contains 541 different structures and 269 references. After a brief historical introduction, the synthesis, reactivity, and nature of the coordinated metals are described along with some properties of these compounds, particularly the complete set of X-ray molecular structures. All of the formulae are represented to show the extraordinary richness of poly(1H-pyrazol-1-yl)methanes and to promote the use of the already known poly(1H-pyrazol-1-yl)methanes in coordination chemistry and the design of new ligands with the reported procedures.

Reformatsky and Blaise reactions in flow as a tool for drug discovery. One pot diversity oriented synthesis of valuable intermediates and heterocycles

L. Huck, M. Berton, A. de la Hoz, A. Díaz-Ortiz, J. Alcázar

Green Chem., 2017, 19, 1420-1424

The application of Reformatsky and Blaise reactions for the preparation of a diverse set of valuable intermediates and heterocycles in a one-pot protocol is described. To achieve this goal, a greener activation protocol for zinc in flow conditions has been developed to introduce this metal efficiently into α-bromoacetates. The organozinc compounds were added to a diverse set of ketones and nitriles to obtain a wide range of functional groups and heterocyclic systems.

Cover of a special issue on Recent advances in flow chemistry in the pharmaceutical industry. Editor: Stefan G. Koenig and Helen F. Sneddon

NMR reaction monitoring in flow synthesis

M.V. Gomez, A. de la Hoz

Beilstein J. Org. Chem. 2017, 13, 285-300.

Recent advances in the use of flow chemistry with in-line and on-line analysis by NMR are presented. The use of macro- and microreactors, coupled with standard and custom made NMR probes involving microcoils, incorporated into high resolution and benchtop NMR instruments is reviewed. Some recent selected applications have been collected, including synthetic applications, the determination of the kinetic and thermodynamic parameters and reaction optimization, even in single experiments and on the μL scale. Finally, software that allows automatic reaction monitoring and optimization is discussed.

Thematic issue on Automated Chemical Synthesis by invitationEditor. Ian R. Baxendale, Marcus Baumann, Richard Bourne

Non-conventional Techniques in Sustainable Flow Chemistry

A. de la Hoz, A. Díaz-Ortiz

Sustainable Flow Chemistry – Chapter 9. Methods and Applications.  Ed. L. Vaccaro, pp. 219-248.

Wiley-VCH

Enabling techniques have undergone significant developments in the past decade and the use of these approaches has modified the way in which organic synthesis is conducted. Continuous-flow processes benefit from facile automation, reproducibility, safety, process reliability and good heat and mass transfer. New synthetic technology platforms, however, are based on the combination of two or more of these enabling techniques. Flow methodologies have been combined with heterogeneous catalysis using supported reagents and scavengers on a wide variety of supports. In addition, neoteric solvents such as supercritical fluids have found a wide range of applications under flow conditions. However, one of the main advantages has been the application of non-conventional techniques for the introduction of energy into reactions, such as microwaves, ultrasound, electrochemistry, photochemistry and inductive heating. This approach provides conditions that are not easily achieved in batch reactions, since energy is transmitted and controlled in different ways in these two systems.

Understanding MAOS through Computational Chemistry

P. Prieto, A. de la Hoz, A. Díaz-Ortiz, A. M. Rodríguez

Chem. Soc. Rev. 2017, 46, 431-451

The importance of microwave irradiation in Organic Synthesis today is unquestionable, but in many cases the nature of these improvements remains unknown. Exploiting the benefits that microwave irradiation has in chemistry is still hindered by a lack of understanding of the physical principles of the interaction of microwave irradiation with the components of a reaction. Moreover, dielectric properties vary with temperature and along the reaction coordinate and this makes the situation more complex. Experimental determinations employed to date in Microwave-Assisted Organic Chemistry (MAOS) are characterized by the importance of thermal heating. In this way the separation of thermal heating from any other effect of the elecromagnetic radiation is completely impossible. This review provides an overview of the use of Computational Chemistry in MAOS to provide a theoretical understanding of the factors that can be used to explain the improvements in MAOS and how computational calculations can be used as a predictive tool.

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.

By invitation of the editors: O. A. Attanasi, P. Merino, D. Spinelli

Tunable emission in aggregated T-Shaped 2H-Benzo[d][1,2,3]triazoles with waveguide behaviour

I. Torres, A. Díaz-Ortiz, L. Sánchez, J. Orduna, M.J. Blesa, J.R. Carrillo, P. Prieto

Dyes Pigments 142 (2017) 212-225

Symmetrical Donor-Acceptor-Donor (D-A-D) 2H-benzo[d][1,2,3]triazole derivatives have been designed by DFT calculations and prepared by a multistep synthetic protocol. The design strategy involved the identification of a suitable acceptor benzotriazole core and modification of the steric volume and donor strength of the branches in order to modulate the Intramolecular Charge Transfer (ICT) process and, consequently, the band gap. Self-assembly of the reported triazoles afforded organized supramolecular structures, the morphologies of which were visualized by SEM imaging. The outcomes demonstrated the effect that the donor moiety has on the emission properties and the morphologies of the aggregates. The aggregates that had a crystal-like structure, with smooth surfaces and flat end facets, exhibited optical waveguide behaviour with tunable colour emission. Depending on the initial design, the different emission wavelengths are related to the band gap of the benzotriazole derivatives.

2016

Diels–Alder reactions in confined spaces: the influence of catalyst structure and the nature of active sites for the retro-Diels–Alder reaction

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.

Thematic issue on Green Chemistry. Editor. L. Vaccaro

New insights in the mechanism of the microwave-assisted Pauson-Khand 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.

Microwave Assisted Green Chemistry

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.

Triazine-Carbon Nanotubes: New Platforms for the Design of Flavin Receptors

M. I. Lucí†o, F. Pichler, J. R. Ramí†rez, A. de la Hoz, A. Sá‚nchez-Migallón, C. Hadad, M. Quintana, A. Giulani, M. V. Bracamonte, J. L. G. Fierro, C. Tavagnacco, M. A. Herrero, M. Prato, E. Vá‚zquez

Chem. Eur.J2016, 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.

Bistriazine-based streptocyanines. Preparation, structural determination and optoelectronic properties

F. León, P. Elizalde, P. Prieto, A. Sánchez-Migallón, A. M. Rodríguez, A. de la Hoz.

Dyes Pigments 2016, 131, 307–319
A series of bistriazine-based streptocyanines has been selectively prepared. A variety of substituents has been introduced into the triazine ring with p-phenylenediamine as a conjugated spacer between the triazine and the streptocyanine moieties. Fukui indices have been used to explain the different sequential reactivity of the chlorine atoms in the triazine ring. 1D- and 2D-DNMR spectroscopy and computational calculations have been carried out to explain the dynamic behavior of these complex systems, which can be explained by the presence of a Cl … H bond. This method was used to build conjugated systems and to show the interaction between the triazine part, the spacer, and the streptocyanine moiety. A study of the optoelectronic properties has been performed by UV–vis and fluorescence spectroscopy. Streptocyanine-based bistriazines are violet-blue emitters and large Stokes shifts of more than 6000 cm−1 were observed. The title compounds showed interesting properties which have potential for use in optoelectronic devices.

Synthesis of Imine-Derived Triazines with Donor-Acceptor Properties

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).

Inside Cover: Stereoselective Synthesis of 1,3-Diaminotruxillic acid derivatives: An Advantageous Combination of CH-ortho-Palladation and on-flow [2+2]-photocycloaddition in microreactors.

Chem. Eur.J2016, 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 C[BOND]H 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.

Stereoselective Synthesis of 1,3-Diaminotruxillic acid derivatives: An Advantageous Combination of CH-ortho-Palladation and on-flow [2+2]-photocycloaddition in microreactors.

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-C[BOND]H bond of the 4-arylidene ring in carboxylic acids. The second step is the [2+2]-photocycloaddition of the C[DOUBLE BOND]C 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.

Green Synthesis of luminescent blue emitters based on bis-triazines with naphthalene as p-conjugated spacer

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.

Self-assembly of T-shape 2H-benzo[d][1,2,3]-triazoles. Optical waveguide and photophysical properties

I. Torres, J. R. Carrillo, A. Díaz-Ortiz, R. Martín, M. V. Gómez, L. Stegemann, C. A. Strassert, J. Orduna, J. Buendía, E. E. Greciano, J. S. Valera, E. Matesanz, L. Sánchez, P. Prieto

RSC Adv., 2016, 6, 36544–36553

T-Shaped 2H-benzo[d][1,2,3]triazole derivatives have been synthesized by Sonogashira coupling reactions under microwave irradiation. DFT calculations were performed in order to understand the structure–property relationships – an aspect that is of vital importance for the rational design of organic selfassemblies for optoelectronic applications. Concentration-dependent 1H Pulse Field-Gradient Spin-Echo (PFGSE) NMR spectroscopy and UV/Vis spectrophotometry indicated the absence of a tendency for the aggregation of single molecules in solution. In contrast, in the solid state these compounds form organized aggregates and these were studied by scanning electron microscopy (SEM), which showed the influence that the peripheral substitution has on the morphology of the aggregates. For example, methoxy-substituted benzotriazoles self-assemble into thick and crystalline needle-like structures. However, the unsubstituted triazoles give rise to flower-like aggregates. Interestingly, the aggregates formed by benzotriazole 1c exhibit waveguide properties.

2015

Microwaves in Green and Sustainable Chemistry.

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

4-Aryl-3,5-bis(arylethynyl)aryl-4H-1,2,4-triazoles: Multitasking Skeleton as a Self-Assembling Unit

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···p 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.

Synthesis of Bright 1H-1,2,4-triazoles. A theoretical and Photophysical Study

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.

Swivel-Cruciform Stilbenes Based on Bithiophene.

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.

4-Aryl-3,5-bis(arylethynyl)aryl-4H-1,2,4-triazoles: Multitasking Skeleton as a Self-assembling Unit.

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 C[BOND]H⋅⋅⋅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.

Influence of Polarity and Activation Energy in Microwave–Assisted Organic Synthesis (MAOS).

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

Determination of kinetic parameters within a single non-isothermal on-flow experiment by Nanolitre-NMR spectroscopy

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.

Solvent-Free Microwave-Assisted Synthesis of 2,5-Dimethoxyphenylaminotriazines

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.

Applications of metal-free 1,2,4-triazole derivatives in materials science.

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.

2014

Multinuclear Nanoliter One-dimensional and Two-dimensional NMR Spectroscopy with a Single Non-resonance

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.

Coenzyme Q10 Protects Human Endothelial Cells from α-Amyloid Induced Uptake and Oxidative Stress-induced Injury.

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.

Isolation and Structure Elucidation of Anthocyanidin 3,7-α-O-diglucosides and Caffeoyl-glucaric Acids from Calafate Berries (Berberis Mycrophylla G. Forst).

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.

Solvent-free Microwave Assisted Synthesis of New 2,4-Dimethoxybenzylaminotriazines

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.

First Example of Alkyl-Aryl Negishi Cross-coupling in Flow: Mild, and Clean Introduction of Functionalized Alkyl Groups

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.

Microwave-Assisted Selective and Efficient Synthesis of 1,3,5-Triazinyl Mono and Bisureas

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.

The Issue of ‘Molecular Radiators’ in Microwave Assisted Reactions. Computational Calculations in Ring Closing Metathesis (RCM).

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.

First Example of a Continuous Flow Carbonylation Reaction Using Aryl Formates as CO Precursors

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.

Microwave Assisted Selective Synthesis of Mono and Bistriazines with Phenylenediamines as Spacers. Study of their Optical Properties.

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.

2013

Optical waveguides from 4-aryl-4H-1,2,4-triazole-based supramolecular structures

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

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Former publications

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