Gas-phase reactivity of Lewis-adducts and model biochemical systems: Quantun Chemistry and Molecular Dynamics perspectives

Tesis doctoral inédita cotutelada por la Université D´Evry Val d´Essone y la Universidad Autónoma de Madrid, Facultad de Ciencias. Departamento de Química. Fecha de lectura: 17-10-2014La reactividad en fase gas, tambin conocida como reactividad intrnseca, tiene un gran interes ya que la ausencia de interacciones con un solvente puede resultar en una reactividad muy diferente, permitiendo adems un mejor concimiento de las propiedades moleculares. Con la aparicin en 1900 de nuevas tcnicas experimenta- les, concretamente tcnicas de ionizacin ms suaves, la qumica de iones en fase gas experiment un desarrollo signi cante con el consecuente cambio en cuanto a nues- tra idea de reactividad qumica. El presente manuscrito est dividido en dos partes diferentes cada una de las cuales trata un aspecto distinto sobre la reactividad en fase gas. La primera parte, Part I, trata sobre el estudio de la acidez intrnseca de una serie de bases de Lewis pertenecientes al grupo 13 de la tabla peridica. EL principal tema de estudio durante esta primera parte son los cambios que se producen en dichas acideces intrnsecas al formase un complejo de Lewis con distintos cidos de Lewis en los que el centro activo es un elemento del grupo 13 de la Tabla peridica. Asi, el origen del aumento de acidez observado al formarse el complejo es raciona- lizado a travs del uso de diferentes mtodos tericos. Se han llevado a cabo calculos DFT y ab intio de alto nivel con el n de calcular los valores tericos para la acidez de las moleculas consideradas. Complementariamente, se usaron mtodos para el anlisis de la poblacin electrnica (AIM, NBO y ELF) con el objetivo de describir los cambios en la con guracin electrnica que se producen al formarse el complejo y que son responsables del observado aumento de acidez. Es importante destacar que parte de los resultados aqu presentados han sido corroborados mediante tcnicas experimentales. La seguna parte, Part II, se centra en el estudio de la reactividad unimole- cular de los iones formamida-M2+ (M = Ca, Sr). En este caso, existan trabajos experimentales disponibles relacionados con el estudio de la reacticvidad inducida por colisin (CID, en sus siglas en ingls) de dichos iones. A lo largo de la segunda parte de este manuscrito, se estudian y caracterizan los mecanismos de fragmen- tacin de ambos iones, empleando para ello distintas tcnicas tericas que son a la vez complementarias entre ellas. El primer paso en este estudio es la evaluacin de distintos mtodos tericos con el objetivo de encontrar el ms adecuado para llevar a cabo clculos ables a la vez que se mantiene el coste computacional lo ms bajo posible. Por un lado, hemos realizado un estudio cintico del proceso de fragmen- tacin usando la teora estadstica conocida como RRKM, con el n de describir la reactividad \lenta" (en una escala de tiempo > fs). Por otro lado, realizamos simulaciones dinmicas que permiten describir la reactividad no estadstica en una escala corta de tiempo (< 2.5 fs). De este modo, usando el descrito procedimiento multi-escala, hemos sido capaces de racionalizar el origen de todos los productos observados en los espectros CID de los iones formamida-Ca2+ y formamida-Sr2+ obtenidos experimentalmente, as como las diferencias entre ellos. En un cuarto capitulo se enumeran y describen brevemente los mtodos utiliza- dos, tanto tericos como experimentales, a lo largo del trabajo presentado en este manuscrito.The so-called intrinsic rectivity (gas-phase reactivity) is of great importance since the absence of interaction with a solvent can result in very di erent reactivity patterns; allowing for a better understanding of molecular properties. With the advent in the 1900s of new experimental techniques, notably soft ionization meth- ods such as electrospray ionization, the gas-phase ion chemistry has signigicantly developped in the last decades of the 1900s with a concomitant change in our view of chemical reactivity. The present manuscript is divide in two di erent parts each one dealing with di erent aspects of gas-phase reactivity. Part I is concerned with the study of the intrinsic acidity of a series of group 15 Lewis base. The changes on the aforementioned intrinsic acidity as the Lewis bases form adducts with group 13 Lewis acid is the main subject of this part. Thus, the origin for the acidity enhancement observed upon adduct formation is rationalized by means of di erent theoretical methods. High-level DFT and ab intio calculations were perfomed in order to compute theoretical acidites of the molecules under survey. Complementary to this, population analysis techniques such as AIM, ELF, and NBO were used to analyze the changes on the electronic con gurations of those molecules and therefore provide with an explanation to the observed acidities. It is worth to stress the fact that part of the results were as well con rmed by means of experimental measurements. Part II focuses in unimolecular reactivity of molecular ions, namely, formamide- M2+ (M = Ca, Sr). In this case, experiments studying the Collision Induced Reac- tivity (CID) of these ions were already performed and through the second part of this manuscript the fragmentation mechanism of both ions are studied and char- acterized using di erent, but complementary, theoretical techniques. It is worth to mention that in a very rst-step, an assessment of di erent methods to perform reliable electronic structure calculations while maintaining the lower possible com- putational cost. On the one hand, a kinetic study of the fragmentation process using the statistical theory, RRKM, to describe the long-time reactivity (> fs). On the other hand, direct dynamics simulations are performed in order to describe the short-time (< 2.5 fs) non-statistical reactivity. This multi-scale approach allowed us to account for all the products observed in the CID experimental spectra of formamide-M2+ (M = Ca, Sr), as well as the di erences between them. In the fourth chapter a summary of the experimental and theoretical proce- dures used to perform the work presented in this manuscript is provided

Evidence of the torsion of a polyene chain in a strongly hindered molecular environment: The ttbP4 crystal

In this work we provide experimental and theoretical evidence that in a molecular environment as restricted as the crystalline phase, the all-trans ttbP4 (1,1,8,8-tetrakis(tert-butyl)octa-1,3,5,7-tetraene) can undergo a conformational change, by rotating around the second single bond, when it is electronically excited to its 11Bu state. Undoubtedly, this is an interesting step to clarify the viability of the torsional mechanism of retinal pigments in the cavity of bacteriorhodopsin as proposed in the vision mechanism. We show that the fluorescence emission of ttbP4 in the crystalline phase is the combination of two bands corresponding to the emission from two different ttbP4 conformers. Theoretical simulations of absorption and emission spectra allowed us to identify the two conformers as: i) the most stable all-trans ttbP4, giving rise to a structured fluorescence band, and ii) the conformer generated by the torsion around the second single bond of ttbP4 polyene chain, giving rise to an emission band with hardly any structure. Interestingly, experimental data also show that the rotated structure, after deactivating to the ground state, takes a time to return to the all-trans configurationThankful to the Universidad Autonoma de Madrid for providing the facility to carry out this research. A.M.S. thanks the CCC-UAM for generous allocation of computing time and the Madrid Government (Comunidad de Madrid-Spain) under the Multiannual Agreement with UAM in the line Support to Young Researchers, in the context of the V PRICIT (SI3-PJI-2021-00463). We acknowledge Javier Cerezo for fruitful discussions and providing help with FCclases3 program to simulate the spectr

Computational Design of a Tetrapericyclic Cycloaddition and the Nature of Potential Energy Surfaces with Multiple Bifurcations

An ambimodal transition state (TS) that leads to formation of four different pericyclic reaction products ([4 + 6]-, [2 + 8]-, [8 + 2]-, and [6 + 4]-cycloadducts) without any intervening minima has been designed and explored with DFT computations and quasiclassical molecular dynamics. Direct dynamics simulations propagated from the ambimodal TS show the evolution of trajectories to give the four cycloadducts. The topography of the PES is a key factor in product selectivity. A good correlation is observed between geometrical resemblance of the products to the ambimodal TS (measured by the RMSD) and the ratio of products formed in the dynamics simulationsWe are grateful to the National Science Foundation (CHE1764328 to K.N.H.) for financial support of this research and for access to XSEDE and UCLA Hoffman 2 for computer time and for this study. A.M.S. thanks the Madrid Government (Comunidad de Madrid-Spain) under the Multiannual Agreement with Universidad Autónoma de Madrid in the line Support to Young Researchers, in the context of the V PRICIT (SI3-PJI-2021-00463) and “Ministerio de Educación Cultura y Deporte” for funding (CAS18/00458

2-Hydroxybenzophenone as a Chemical Auxiliary for the Activation of Ketiminoesters for Highly Enantioselective Addition to Nitroalkenes under Bifunctional Catalysis

An organocatalytic system is presented for the Michael addition of monoactivated glycine ketimine ylides with a bifunctional catalyst. The ketimine bears an ortho hydroxy group, which increases the acidity of the methylene hydrogen atoms and enhances the reactivity, thus allowing the synthesis of a large variety of a,g-diamino acid derivatives with excellent stereoselectivit

Enhancing visible-light photocatalysis via endohedral functionalization of single-walled carbon nanotubes with organic dyes

The encapsulation of an organic dye, 10-phenylphenothiazine (PTH), in the inner cavity of single-walled carbon nanotubes (SWNTs) as a breaking heterogenization strategy is presented. The PTH@oSWNT material was microscopically and spectroscopically characterized, showing intense photoemission when illuminated with visible light at the nanoscale. Thus, PTH@oSWNT was employed as a heterogeneous photocatalyst in single electron transfer dehalogenation reactions under visible light irradiation. The material showed an enhanced photocatalytic activity, achieving turnover numbers as high as 3200, with complete recyclability and stability for more than eight cycles. Computational calculations confirm that electronic communication between both partners is established because, upon illumination, an electron of the excited PTH is transferred from the πsystem of the molecule to the delocalized π-cloud of the SWNT, thus justifying the enhanced photocatalytic activityFinancial support was provided by the European Research Council (ERC-CoG, contract number: 647550), the Spanish Government (RTI2018-095038-B-I00, PID2019-110091GB-I00), and the “Comunidad de Madrid” and European Structural Funds (S2018/NMT-4367). M.B. wishes to thank the Spanish Government for a Juan de la Cierva contract (IJC2019-042157-I). A.M.-S. acknowledges support by the Comunidad Autónoma de Madrid under grant 2016-T2/IND166

Intramolecular hydrogen bond activation for kinetic resolution of furanone derivatives by an organocatalyzed [3+2] asymmetric cycloaddition

Herein, a formal highly enantioselective organocatalyzed [3+2] cycloaddition of furanone derivatives and azomethine ylides is presented. The success of this reaction resides in an intramolecular hydrogen bond activation through an o-hydroxy group at aromatic ring of the imine, allowing the formation of highly multifunctional bicyclic adducts with five stereogenic centers in a stereocontrolled manner. Furthermore, the reaction is paired to a highly efficient kinetic resolution of butenolides, achieving selectivity factors above 200. Using this methodology, furan-2(5H)-ones as well as furo[3,4-c]pyrrolidinones were obtained with high enantioselectivities. Quantum chemistry calculations reveal the crucial role of hydrogen bond formed between the catalyst donor-units and the two reagents, which modify their arrangement and promote effective facial discrimination resulting in a highly selective kinetic resolution. In addition, further applicability of the kinetic resolution process is shownPID2019-110091GB-I00, PID2021-122299NB-I00, TED2021-130470B-I00, TED2021-129999B-C32, “Comunidad de Madrid” for European Structural Funds (S2018/NMT-4367) and (Y2020/NMT6469), CEX2018-000805-

Intramolecular hydrogen-bond activation for the addition of nucleophilic imines: 2-hydroxybenzophenone as a chemical auxiliary

The addition of nucleophilic imines, using 2-hydroxybenzophenone as a chemical auxiliary, is presented. An intramolecular six-membered ring via hydrogen bonding that enhances the reactivity and selectivity is the key of this strategy, which is supported by DFT calculations and experimental trialsSpanish Government (CTQ2015-64561-R, CTQ2016-76061-P, and MDM-2014-0377), Prodep (UJAT-PTC-247) and CCC-UAM are acknowledged. A. G. thanks MINECO for a PhD fellowship (FPI) and A. M. S. thanks CAM for a postdoctoral contract (2016-T2/IND-1660

Boron Dipyrromethene (BODIPY) as Electron-Withdrawing Group in Asymmetric Copper-Catalyzed [3+2] Cycloadditions for the Synthesis of Pyrrolidine-Based Biological Sensors

This is the peer reviewed version of the following article: Rigotti, T., Asenjo‐Pascual, J., Martín‐Somer, A., Milán Rois, P., Cordani, M., Díaz‐Tendero, S., ... & Alemán. Boron Dipyrromethene (BODIPY) as Electron‐Withdrawing Group in Asymmetric Copper‐Catalyzed [3+ 2] Cycloadditions for the Synthesis of Pyrrolidine‐Based Biological Sensors. Advanced Synthesis & Catalysis Volume 362, Issue 6, 17 March 2020, Pages 1345-1355 , which has been published in final form at https://doi.org/10.1002/adsc.201901465. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsIn this work, we describe the use of Boron Dipyrromethene (BODIPY) as electron-withdrawing group for activation of double bonds in asymmetric copper-catalyzed [3+2] cycloaddition reactions with azomethine ylides. The reactions take place under smooth conditions and with high enantiomeric excess for a large number of different substituents, pointing out the high activation of the alkene by using a boron dipyrromethene as electron-withdrawing group. Experimental, theoretical studies and comparison with other common electron-withdrawing groups in asymmetric copper-catalyzed [3+2] cycloadditions show the reasons of the different reactivity of the boron dipyrromethene derivatives, which can be exploited as a useful activating group in asymmetric catalysis. Additional experiments show that the so obtained pyrrolidines can be employed as biocompatible biosensors, which can be located in the endosomal compartments and do not present toxicity in three cell linesThis work was supported by the Spanish Government (RTI2018‐095038‐B‐I00, CTQ2016‐76061‐P, SAF2017‐87305‐R), Comunidad de Madrid (IND2017/IND‐7809), and co‐financed by European Structural and Investment Fund. We acknowledge the generous allocation of computing time at the CCC (UAM). Financial support from the Spanish Ministry of Economy and Competitiveness, through the ‘‘Maria de Maeztu’’ Program of Excellence in R&D (MDM‐2014‐0377), is also acknowledged. Asociación Española Contra el Cáncer, and IMDEA Nanociencia acknowledge support from the ′Severo Ochoa′ Programme for Centres of Excellence in R&D (MINECO, Grant SEV‐2016‐0686). P.M.R thanks the Ministry of Economy, Industry and competitiveness of Spain for the FPI grant (BES‐2017.082521). A.M.S. thanks CAM for a postdoctoral contract (2016‐T2/IND‐1660

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

International audienceMultisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1 , OAS2 , or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)–sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the single-stranded RNA–degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L–deficient cells. Cytokine production in RNase L–deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C