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Publications 2014

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.