Desarrollo de catalizadores basados en ligandos NHC funcionalizados con aplicación en procesos químicos sostenibles

El trabajo desarrollado en esta Memoria se ha centrado en la síntesis, caracterización y estudio de las posibles aplicaciones en catálisis de compuestos organometálicos de rodio, iridio, cobre y manganeso que contienen ligandos tridentados basados en el esqueleto central de la 2,6-lutidina doblemente funcionalizado asimétricamente. Los ligandos, de fórmula general NHC-Py-L, poseen un fragmento NHC en uno de los brazos laterales del fragmento 2,6-lutidina y un grupo dador L potencialmente hemilábil (L = OMe, NEt2, NHtBu) en el otro. Se han preparado una serie de compuestos neutros y catiónicos de rodio(I) e iridio(I) que incorporan la diolefina 1,5-ciclooctadieno y los ligandos NHC funcionalizados coordinados de forma monodentada, bidentada ó tridentada. El estudio de la reactividad de estos compuestos con monóxido de carbono y dihidrógeno han permitido acceder a compuestos con una gran variedad estructural, algunos de ellos con el ligando NHC coordinado de forma pincer. Adicionalmente, se han sintetizado compuestos de rodio(III) e iridio(III) en los que se ha producido una activación C-H de uno de los metilos del grupo t-butilo del ligando NHC, lo que resulta en una coordinación tetradentada del ligando NHC-Py-L. Asimismo, se han sintetizado compuestos catiónicos de manganeso(I) con los ligandos coordinados de forma pincer y compuestos de cobre(I) que presentan una estructura polimérica en estado sólido y previsiblemente tetranuclear en disolución.Los compuestos de iridio sintetizados son catalizadores eficientes en los procesos de autotransferencia de hidrógeno de β-alquilación de alcoholes y N-alquilación de aminas con alcoholes primarios. Además, estos compuestos de iridio(I) proporcionan excelentes resultados en reacciones de N-metilación de aminas y de nitrocompuestos con metanol que actúa como fuente C1 y como disolvente. Estudios experimentales han demostrado la importancia de los procesos de cooperación metal-ligando (MLC), por desaromatización/aromatización del anillo de piridina, en la preactivación del catalizador y en el ciclo catalítico operante facilitando la generación de especies metal-hidruro activas por activación del alcohol correspondiente. Por otra parte, los compuestos de rodio se han aplicado en reacciones de hidrosililación de alquinos, tanto terminales como internos, con buena selectividad al derivado β(Z)-vinilsilano. Ha sido posible identificar especies Rh(III)-H por adición oxidante del silano al precursor de catalizador lo que sugiere que las reacciones transcurren a través de un mecanismo Chalk-Harrod modificado. Se han preparado polímeros de coordinación de cobre(I) que son extraordinariamente eficientes en la reacción de cicloadición [3+2] de azidas y alquinos lo que ha permitido la preparación de 1,2,3-triazoles sustituidos en las posiciones 1 y 4 utilizando un amplio rango de alquinos. Por último, los compuestos de manganeso(I) son moderadamente activos en la hidrosililación de CO2 a sililformiato. La gran actividad y selectividad mostrada por los catalizadores en los procesos catalíticos objeto de estudio ha permitido disminuir la carga de catalizador de iridio a valores del 0.1 mol% en las reacciones de β-alquilación y N-alquilación, y a valores en el rango de 0.5-2.5 mol% en las reacciones de N-metilación de aminas y nitro derivados. En el caso de las reacciones de cicloadición [3+2] de azidas y alquinos la carga de catalizador de cobre puede reducirse hasta el 0.0025 mol% (25 ppm) con tiempos de reacción aceptables. En consecuencia, los catalizadores basados en ligandos NHC-Py-L están a la altura de los sistemas más activos previamente descritos en la bibliografía.<br /

N-Methylation of Amines with Methanol Catalyzed by Iridium(I) Complexes Bearing an N, O-Functionalized NHC Ligand

A set of neutral IrBr(L-2)-(kappa C-(t)BuImCH(2)PyCH(2)OMe)] and cationic Ir(L-2)-(kappa C, N-tBuImCH(2)PyCH(2)OMe)]PF6 (L-2 = cod, (CO)(2)) Ir(I) compounds featuring a flexible lutidine-derived polydentate ligand having NHC and - OMe as donor functions have been evaluated as catalyst precursors for the N-methylation of aniline using methanol both as a reducing agent and a C1 source. The carbonyl complexes are somewhat more active than the related diene compounds with the neutral compound IrBr(CO)(2)(kappa C-(t)BuImCH(2)PyCH(2)OMe)] being the more active. A range of aromatic primary amines, including heterocyclic amines, have been selectively transformed into the corresponding N-methylamino derivatives using this catalyst at a low catalyst loading (0.1 mol %) and substoichiometric amounts of Cs2CO3 (half equiv) as a base, in methanol at 423 K. For aliphatic primary amines, selective N, N-dimethylation was achieved under the same catalytic conditions. The unselective deprotonation of the methylene linkers in IrBr(CO)(2)(kappa C-(t)BuImCH(2)PyCH(2)OMe)] affords two isomeric neutral complexes featuring a coordinated dearomatized pyridine core, which were converted into Ir(OMe)(CO)(2)(kappa C-(t)BuImCH(2)PyCH(2)OMe)] upon addition of methanol. This compound undergoes thermal activation of a C-H bond of the tert-butyl group to give the cyclometalated iridium(I) complex Ir(CO)(2){kappa C-2, C-(-CH2Me2C-ImCH(2)PyCH(2)OMe)}] featuring a bidentate C, C-coordinated NHC ligand. Mechanistic investigations support a borrowing hydrogen mechanism proceeding through iridium(I) intermediates with the methoxo complex as the catalytic active species and the cyclometalated complex as the catalyst resting state. Deuterium labeling experiments have demonstrated that both species are in equilibrium under catalytic conditions, which is consistent with the exhibited catalytic activity of the cyclometalated complex

Effective N-methylation of nitroarenes with methanol catalyzed by a functionalized NHC-based iridium catalyst: a green approach to N-methyl amines

Compound [IrBr(CO)2(κC-tBuImCH2PyCH2OMe)] featuring a flexible pyridine/OMe functionalized NHC ligand κ1C coordinated efficiently catalyzes the selective N-monomethylation of nitroarenes using methanol as both the reducing agent and the C1 source. A range of functionalized nitroarenes including heterocyclic or sterically hindered derivatives have been efficiently converted to the corresponding N-monomethyl amines in good yields at low catalyst loadings using sub-stoichiometric amounts of Cs2CO3 as a base. Mechanistic investigations support a borrowing-hydrogen mechanism in which methanol acts as the hydrogen source and methylating agent. Further, the hydrogen transfer reduction of nitrobenzene to aniline under optimized reaction conditions should proceed through a direct mechanism involving nitrosobenzene and N-phenylhydroxylamine intermediates.Financial support from the Ministerio de Ciencia e Innovación (MICINN/FEDER) under the Project CTQ2016-75884-P and the Regional Government of Aragón/FEDER 2014-2020 “Building Europe from Aragón” (group E42_17R) is gratefully acknowledged. M. G.-L. thanks MINECO for a predoctoral fellowship (BES-2014-069624).Peer reviewe

Catalizadores de Iridio basados en ligandos pincer NHC activos en reacciones de autotransferencia de Hidrógeno

Resumen del póster presentado al XIII Simposio de Investigadores Jóvenes de la Real Sociedad Española de Química Sigma-Aldrich, celebrado en Logroño del 8 al 11 de noviembre de 2016.El desarrollo de catalizadores homogéneos está asociado al diseño de ligandos capaces de modificar las propiedades del centro metálico con el objetivo de producir transformaciones más sostenibles. En este contexto, los complejos de metales de transición que contienen ligandos carbeno N-heterocíclicos (NHC) han demostrado ser la plataforma adecuada para el diseño de catalizadores en procesos químicos sostenibles. En el presente trabajo se han diseñado catalizadores de Ir con arquitecturas tipo pincer basadas en un esqueleto piridina-NHC-grupo hemilábil que tienen el potencial de activar procesos de cooperación metal-ligando a través de la aromatización/desaromatización del anillo de piridina. Esta nueva familia de catalizadores presenta una gran actividad en reacciones de autotransferencia de hidrógeno (β-alquilación y N-alquilación) con completa conversión y buena selectividad en cortos periodos de tiempo.Peer Reviewe

ß-(Z)-Selective alkyne hydrosilylation by a N,O-functionalized NHC-based rhodium(i) catalyst

Neutral and cationic cyclooctadiene rhodium(I) complexes with a lutidine-derived polydentate ligand having NHC and methoxy side-donor functions, [RhBr(cod)(κC-tBuImCH2PyCH2OMe)] and [Rh(cod)(κ2C,N-tBuImCH2PyCH2OMe)]PF6, have been prepared. Carbonylation of the cationic compound yields the dicarbonyl complex [Rh(CO)2(κ2C,N-tBuImCH2PyCH2OMe)]PF6 whereas carbonylation of the neutral compound affords a mixture of di- and monocarbonyl neutral complexes [RhBr(CO)2(κC-tBuImCH2PyCH2OMe)] and [RhBr(CO)(κ2C,N-tBuImCH2PyCH2OMe)]. These complexes efficiently catalyze the hydrosilylation of 1-hexyne with HSiMe2Ph with a marked selectivity towards the β-(Z)-vinylsilane product. Catalyst [RhBr(CO)(κ2C,N-tBuImCH2PyCH2OMe)] showed a superior catalytic performance, in terms of both activity and selectivity, and has been applied to the hydrosilylation of a range of 1-alkynes and phenylacetylene derivatives with diverse hydrosilanes, including HSiMe2Ph, HSiMePh2, HSiPh3 and HSiEt3, showing excellent β-(Z) selectivity for the hydrosilylation of linear aliphatic 1-alkynes. Hydrosilylation of internal alkynes, such as diphenylacetylene and 1-phenyl-1-propyne, selectively affords the syn-addition vinylsilane products. The β-(Z) selectivity of these catalysts contrasts with that of related rhodium(I) catalysts based on 2-picolyl-functionalised NHC ligands, which were reported to be β-(E) selective. An energy barrier ΔG‡ of 19.8 ± 2.0 kcal mol−1 (298 K) has been determined from kinetic studies on the hydrosilylation of 1-hexyne with HSiMe2Ph. DFT studies suggest that the methoxy-methyl group is unlikely to be involved in the activation of hydrosilane, and then hydrosilane activation is likely to proceed via a classical Si–H oxidative addition

Mechanistic studies on the N -alkylation of amines with alcohols catalysed by iridium(i) complexes with functionalised N-heterocyclic carbene ligands

Iridium(i) cyclooctadiene complexes featuring O- and N-donor functionalised NHC ligands efficiently catalyse the C-N coupling of amines with alcohols through a borrowing hydrogen mechanism. These catalysts have been applied for the N-alkylation of several aromatic and aliphatic primary amines with a range of alcohols including benzyl alcohol derivatives, straight-chain primary alcohols and secondary alcohols. The cationic complex [Ir(NCCH)(cod){MeIm(2-methoxybenzyl)}] (cod = 1,5-cyclooctadiene, MeIm = 3-methylimidazol-2-ylidene) having a rigid O-donor wingtip exhibits the best catalytic performance for the N-alkylation of aniline with benzyl alcohol giving a quantitative conversion to N-benzylaniline in 3 h. Experimental and theoretical studies at the DFT level on the N-alkylation of aniline with benzyl alcohol catalysed by the model compound [IrCl(cod)(IMe)] (IMe = 1,3-dimethyl-imidazol-2-ylidene) support the participation of the iridium catalyst not only in the alcohol dehydrogenation and imine hydrogenation steps but also in the key step leading to the formation of the new C-N bond. Nucleophilic attack of an iridium-amido species generated in basic medium on the electrophilic aldehyde results in a hemiaminolate intermediate species from which the hemiaminal is released by alcoholysis. The free hemiaminal dehydrates to give the corresponding intermediate imine product that is hydrogenated by the iridium catalyst to the N-alkylated amine product. The iridium(i) complexes featuring functionalised NHC ligands are more active than [IrCl(cod)(IMe)] which highlights the positive influence of the functional group on the N-alkylation catalytic activity.Financial support from the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER, Projects CTQ2013-42532-P and CTQ2016-75884-P) and the Diputación General de Aragón (DGA/FSE-E07) is gratefully acknowledged.Peer Reviewe

An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations

Establishing the genotypes of patients with hyperphenylalaninemia (HPA)/phenylketonuria (PKU, MIM#261600) has been considered a cornerstone for rational medical management. However, knowledge of the phenylalanine hydroxylase gene (PAH) mutational spectrum in Latin American populations is still limited. Herein, we aim to update the mutational PAH spectrum in the largest cohort of HPA/PKU Mexican patients (N = 124) reported to date. The biallelic PAH genotype was investigated by Sanger automated sequencing, and genotypes were correlated with documented biochemical phenotypes and theoretical tetrahydrobiopterin (BH4) responsiveness. Patients were biochemically classified as having classic PKU (50%, 62/124), mild PKU (20.2%, 25/124) and mild HPA (29.8%, 37/124). Furthermore, 78.2% of the included patients (97/124) were identified by newborn screening. A total of 60 different pathogenic variants were identified, including three novel ones (c. 23del, c. 625_626insC and c. 1315 + 5_1315 + 6insGTGTAACAG), the main categories being missense changes (58%, 35/60) and those affecting the catalytic domain (56.6%, 34/60), and c. 60 + 5G &gt; T was the most frequent variant (14.5%, 36/248) mainly restricted (69.2%) to patients from the central and western parts of Mexico. These 60 types of variants constituted 100 different biallelic PAH genotypes, with the predominance of compound-heterozygous ones (96/124, 77%). The expected BH4 responsiveness based on the PAH genotype was estimated in 52% of patients (65/124), mainly due to the p. (Val388Met) (rs62516101) allele. Instead, our study identified 27 null variants with an allelic phenotype value of zero, with a predominance of c. 60 + 5G &gt; T, which predicts the absence of BH4 responsiveness. An identical genotype reported in BIOPKUdb was found in 92/124 (74%) of our patients, leading to a genotype&ndash;phenotype concordance in 80/92 (86.9%) of them. The high number of variants found confirms the heterogeneous and complex mutational landscape of HPA/PKU in Mexico

Mutational spectrum of PTS gene and in silico pathological assessment of a novel variant in Mexico

BACKGROUND Tetrahydrobiopterin (BH4) is the cofactor for 6-pyruvoyl-tetrahydropterin synthase (PTPS); it is involved in BH4 biosynthesis and is encoded by PTS gene. Its deficiency (PTPSD) is characterized by hyperphenylalaninemia (HPA) and deficit in central monoamine neurotransmitters. We describe the clinical and mutational spectrum of five patients with PTPSD, from four unrelated Mexican families. All patients had symptomatic diagnosis and presented severe early neurological manifestations and HPA. METHODS Clinical and biochemical data from studied patients were recorded. Responsible PTPSD genotypes was determined by direct and bidirectional Sanger DNA sequencing of the six PTS coding exons and their exon-intron borders, and these were directly searched in the available relatives. The novel PTS missense variant [NM_3000317.2:331G > T, p.(Ala111Ser)] was subjected to in silico, to predict a possible deleterious effect. RESULTS Diminished fetal movements were perceived as a uniform characteristic in the studied group. DNA sequencing showed two known p.(Arg25∗) and p.(Val132TyrFs∗19) and the novel missense p.(Ala111Ser) PTS variants, the latter representing potentially a frequent PTPSD-responsible allele (50%, 4/8) in Mexican patients. In silico protein modeling analysis of the p.(Ala111Ser) variant revealed loss of hydrophobic interactions between the alanine and neighboring valines, suggesting that these changes in polarity may be detrimental for enzyme function, structure and/or stability. CONCLUSIONS This work contributes to the knowledge of PTPS molecular spectrum. The delayed diagnosis of these patients emphasizes the importance of considering BH4 metabolism defects in the differential diagnosis of HPA, especially for countries that are beginning their HPA newborn screening programs

Observations of the Crab Nebula and Pulsar with the large-sized telescope prototype of the Cherenkov telescope array

The Cherenkov Telescope Array (CTA) is a next-generation ground-based observatory for gamma-ray astronomy at very high energies. The Large-Sized Telescope prototype (LST-1) is located at the CTA-North site, on the Canary Island of La Palma. LSTs are designed to provide optimal performance in the lowest part of the energy range covered by CTA, down to ≃20 GeV. LST-1 started performing astronomical observations in 2019 November, during its commissioning phase, and it has been taking data ever since. We present the first LST-1 observations of the Crab Nebula, the standard candle of very-high-energy gamma-ray astronomy, and use them, together with simulations, to assess the performance of the telescope. LST-1 has reached the expected performance during its commissioning period—only a minor adjustment of the preexisting simulations was needed to match the telescope's behavior. The energy threshold at trigger level is around 20 GeV, rising to ≃30 GeV after data analysis. Performance parameters depend strongly on energy, and on the strength of the gamma-ray selection cuts in the analysis: angular resolution ranges from 0fdg12–0fdg40, and energy resolution from 15%–50%. Flux sensitivity is around 1.1% of the Crab Nebula flux above 250 GeV for a 50 hr observation (12% for 30 minutes). The spectral energy distribution (in the 0.03–30 TeV range) and the light curve obtained for the Crab Nebula agree with previous measurements, considering statistical and systematic uncertainties. A clear periodic signal is also detected from the pulsar at the center of the Nebula.Agencia Estatal de Investigación (España)"Centro de Excelencia Severo Ochoa" programGobierno de España"Unidad de Excelencia Maria de Maeztu" program"Juan de la Cierva Incorporacion" program"Atraccion de Talento" program of Comunidad de MadridComunidad de MadridRecovery, Transformation and Resilience Plan from the Spanish StateLa Caixa FoundationJunta de AndaluciaPAIDI 2020Consejeria de Economia, Industria, Comercio y Conocimiento del Gobierno de CanariasGeneralitat de CatalunyaDepto. de Estructura de la Materia, Física Térmica y ElectrónicaFac. de Ciencias FísicasTRUEpu

Development and validation of a predictive model of in-hospital mortality in COVID-19 patients.

We retrospectively evaluated 2879 hospitalized COVID-19 patients from four hospitals to evaluate the ability of demographic data, medical history, and on-admission laboratory parameters to predict in-hospital mortality. Association of previously published risk factors (age, gender, arterial hypertension, diabetes mellitus, smoking habit, obesity, renal failure, cardiovascular/ pulmonary diseases, serum ferritin, lymphocyte count, APTT, PT, fibrinogen, D-dimer, and platelet count) with death was tested by a multivariate logistic regression, and a predictive model was created, with further validation in an independent sample. A total of 2070 hospitalized COVID-19 patients were finally included in the multivariable analysis. Age 61-70 years (p80 years (p2 ULN (p = 0.003; OR: 1.79; 95%CI: 1.22 to 2.62), and prolonged PT (p<0.001; OR: 2.18; 95%CI: 1.49 to 3.18) were independently associated with increased in-hospital mortality. A predictive model performed with these parameters showed an AUC of 0.81 in the development cohort (n = 1270) [sensitivity of 95.83%, specificity of 41.46%, negative predictive value of 98.01%, and positive predictive value of 24.85%]. These results were then validated in an independent data sample (n = 800). Our predictive model of in-hospital mortality of COVID-19 patients has been developed, calibrated and validated. The model (MRS-COVID) included age, male gender, and on-admission coagulopathy markers as positively correlated factors with fatal outcome