A fully diastereoselective oxidation of a mesoionic dipole with triplet molecular oxygen.

Oxidations with molecular oxygen are ubiquitous processes in biological systems where cofactor-dependent enzymes activate either oxygen or hydrogen peroxide to induce multichannel pathways. In stark contrast, such slow atmospheric oxidations are seldom harnessed in chemical synthesis and analysis. The present study unveils an unusual aerobic oxidation of a mesoionic dipole leading easily to a more functionalized skeleton. Although the synthetic scope has not been explored, two key considerations emerge from this transformation, as it proceeds with complete diastereoselection and could be successfully extrapolated to structurally related mesoionic chirons without racemization. How this oxidation actually occurs proved to be puzzling from the onset and only high-level computation reveals a cascade transformation, whose results reconcile theory and experiment. Hopefully, the mechanistic insights should help us to understand better the autoxidative reactions of organic molecules.

On the dual reactivity of a Janus-type mesoionic dipole: experiments and theoretical validation.

A mesoionic bicycle, easily synthesized from a proteinogenic amino acid, l-leucine, behaves as both thiazolium-olate and diazolium-olate dipoles, as unveiled by its dipolar cycloadditions. This chameleonic reactivity has been thoroughly interpreted by dissecting the mechanistic landscape aided by the distortion-interaction model.

Mechanistic studies of 1,3-dipolar cycloadditions of bicyclic thioisomünchnones with alkenes. A computational rationale focused on donor-acceptor interactions.

This paper describes a mechanistic study, with the interplay of experiment and theory, on the cycloadditions of a bicyclic mesoionic 1,3-dipole versus a series of representative symmetrical (1-phenyl-1H-pyrrole-2,5-dione and dimethyl maleate) and asymmetrical [(E)-(2-nitrovinyl)benzene, acrylonitrile, and but-3-en-2-one] olefinic dipolarophiles. These results allow a comparative analysis with monocyclic dipoles and open further avenues to structurally diversified heteroatom-rich rings. The unichiral version of the bicyclic dipole leads to adducts containing up to five chiral centers, whose formation proceeds with high levels of facial stereoinduction in reactions involving bulky dipolarophiles. The second and largest part of this study provides a theoretical interrogation on the pericyclic mechanism with DFT-methods [M06-2X/6-311++G(d,p)]. In order to get further mechanistic insights, we have also explored charge transfers between reaction partners using NBO analysis, which satisfactorily justifies the stereochemical outcome.

Computational Screening of New Orthogonal Metal-Free Dipolar Cycloadditions of Mesomeric Betaines.

Computational strategies have gained increasing impact in the de novo design of large molecular sets targeted to a desired application. Herein, DFT-assisted theoretical analyses of cycloadditions, involving mesoionic dipoles and strained cycloalkynes, unveil a series of unexplored mesomeric betaines as vastly superior candidates for orthogonal applications. Thus, isosydnones; thiosydnones; and a six-membered homolog, 6-oxo-1,3-oxazinium-4-olate, exhibit enhanced reactivity with respect to sydnone, which is the archetypal mesoionic ring employed so far in orthogonal chemistry. These compounds were found by assessing energy barriers and transition structures, which are largely governed by electron fluxes from dipolarophile to dipole and noncovalent interactions. Charge-transfer analysis also accounts for previous experimental and theoretical results gathered in the literature, and provides a rationale for further substitution variations. The above naked dipoles release only CO2 as a byproduct through retro-Diels-Alder of the resulting cycloadducts. These results should invite practitioners to look at such underestimated dipoles and could also help to minimize the number of experiments.

Prebiotic-Like Condensations of Cyanamide and Glyoxal: Revisiting Intractable Biotars.

We report a detailed investigation into the nature of products that are generated by the reactions of cyanamide and glyoxal, two small molecules of astrochemical and prebiotic significance, under different experimental conditions. The experimental data suggest that the formation of oligomeric structures is related in part to the formation of insoluble tholins in the presence of oxygen-containing molecules. Although oligomerization proceeds well in water, product isolation turned out to be impractical. Instead, solid precipitates were obtained easily in acetone. Crude mixtures have been thoroughly scrutinized by spectroscopic methods, in particular NMR and mass spectroscopy (ESI mode), which are all consistent with the generation of a few functional groups that are embedded into regular chains of five- and six-membered rings, thereby pointing to a supramolecular organization. Three different models of cross-condensation and chain growth are suggested. These synthetic explorations provide further insights into the formation of complex organic matter in interstellar scenarios and extraterrestrial bodies that might have played a pivotal role in chemical evolution.

On the Plausibility of Pseudosugar Formation in Cometary Ices and Oxygen-rich Tholins.

We revisit herein the formation and structure of dihydroxy dioxanes, which can be obtained from prebiotically available precursors and can be regarded as primeval sugar surrogates. Previous studies dealing with the heterogeneous composition of interstellar bodies point to the existence of significant amounts of small polyalcohols along with oxygen-containing oligomers. Even though such derivatives did not give rise to nucleosides and oligonucleotides, nor they were incorporated into subsequent metabolic routes, molecular chimeras based on sugar-like species could be opportunistic scaffolds in pre-evolutionary scenarios. We could figure out that pseudosugars, assembled by hemiacetalic bonds from available precursors in both interstellar and terrestrial scenarios, were presumably more abundant than thought. Moreover, these species share some key features with naturally-occurring sugar rings, such as anomeric preferences, coordinating ability, and the prevalent occurrence of racemic compounds.

Rethinking aromaticity in H-bonded systems. Caveats for transition structures involving hydrogen transfer and π-delocalization.

Monoaza- and diaza-derivatives of malondialdehydes, in short aminoacroleins and vinamidines, are prototypical examples of open-chain structures prone to π-electron delocalization, for which intramolecular hydrogen bonding enhances (or diminishes) their pseudoaromaticity depending on the substitution pattern. This interplay is illustrated herein by DFT-based calculations of aromaticity indices in the gas phase and polar solvents. Elucidation of transition structures involved in tautomeric conversions helps to solve how the intramolecular hydrogen transfer occurs. While TSs exhibit a high degree of aromaticity, the dichotomy between forward and backward pathways points to a complex trajectory. Addition of thermal corrections to the electronic energy decreases both the enthalpy and free energy leading to negative ΔH(‡) and ΔG(‡) values. This variational effect accounts for the otherwise elusive distinction between transition structures and saddle points (usually overlooked for high electronic barriers). Also, this rationale fits well within the framework of Marcus' theory.

Pseudo-cyclic structures of mono- and di-azaderivatives of malondialdehydes. Synthesis and conformational disentanglement by computational analyses.

Mono- and diaza-derivatives of malondialdehydes, namely 3-alkyl(aryl)amino-2-arylacroleins and 1,5-dialkyl(aryl)-3-arylvinamidines are open-chain systems in which extended electron delocalization and pseudoaromaticity can be envisaged. A set of diversely functionalized compounds has been synthesized and characterized by spectroscopic data and X-ray diffractometry. Quantum-chemical calculations were performed for all possible neutral tautomers and conformers in the gas phase and compared to those in polar solvents (CHCl3, DMSO, and EtOH) at the M06-2X/6-311++G(d,p) level. Tautomeric equilibria and conformational preferences can be rationalized in terms of structural factors, which can be roughly estimated as summation or subtractions of intramolecular interactions. As expected, a key role is played by intramolecular hydrogen bonds whose strength varies from the gas phase to polar ethanol. This issue also delves into the concept of resonance-assisted H-bond, where the donor and acceptor atoms are connected by a π-conjugated system. The most stable conformers (structures a and c) possess a high degree of pseudoaromaticity as inferred from HOMA indexes and other delocalization parameters.

Stepwise formation of 1,3-diazolium-4-thiolates by münchnone cycloadditions: promising candidates for nonlinear optics.

An improved preparation of mesoionic heterocycles 1,3-diazolium-4-thiolates by [3 + 2] cycloadditions of münchnones with aryl isothiocyanates is reported. The process takes place with high or complete regioselectivity, and fast and clean transformations are observed under microwave heating in DMF. DFT calculations support that this cycloaddition proceeds preferably through a stepwise mechanism. Given the pattern substitution around the mesoionic ring resulting in a push-pull system, theoretical estimations predict large hyperpolarizabilities in some cases, which is typical of molecules exhibiting nonlinear optical responses.

On the prebiotic synthesis of D-sugars catalyzed by L-peptides: assessments from first-principles calculations.

What accounts for a particular chiral selection in the case of a few sugars of prebiotic relevance, thereby mirroring the asymmetry observed in nature? By using first-principles calculations, the generation of pentoses from glycolaldehyde (the initial product of the autocatalytic formose reaction), which has been detected in outer space), has been modeled by using L-Val-L-Val as a primeval catalyst. Our theoretical study provides insight into the mechanism of this reaction and satisfactorily explains a few key molecular events. Our rationale agrees with the reported experimental data and shows that the D-configuration is only favored for ribose. L-pentoses are usually favored in the presence of L-configured dipeptides, as observed experimentally, although no chiral selection could be observed in the case of xylose. These results confirm that a prebiotic sugar soup could be fine-tuned in the presence of shorter peptides as catalysts and that D-ribose would have also resulted in an advantageous imbalance for further amplification and chemical evolution.

Catheter ablation of accessory pathway in the treatment of pacemaker-mediated tachycardia.

Pacemaker-mediated tachycardia (PMT) remains a clinical problem in patients with dual-chamber pacemaker despite technological advances. The onset mechanism of this tachycardia is sensing of retrograde atrial activation after ventricular stimulation. Repeated retrograde conduction perpetuates tachycardia. Postventricular atrial refractory period prolongation has been used for prevention of PMT, but this is not the solution in all cases. We present a case with PMT where the retrograde limb is a left accessory pathway, which is treated with radiofrequency ablation successfully.

Tautomerism in Schiff bases. The cases of 2-hydroxy-1-naphthaldehyde and 1-hydroxy-2-naphthaldehyde investigated in solution and the solid state.

Schiff bases derived from hydroxyl naphthaldehydes and o-substituted anilines have been prepared and their tautomerism assessed by spectroscopic, crystallographic, and computational methods. Tautomeric equilibria have also been studied and reveal in most cases a slight preference of imine tautomers in solution; a fact supported by DFT calculations in the gas phase as well as incorporating solvent effects through the SMD model. To simulate the effect exerted by the crystal lattice on tautomer stability, we have developed a computational protocol in the case of 1-tert-butyl-2-(2-hydroxy-1-naphthylmethylene)aminobenzene whose data have been obtained experimentally at 120 K. Although a rapid imine-enamine interconversion may be occurring in the solid state, the imine tautomer becomes the most stable form and the energy difference should be related to the difference in the packing of the molecules.

On the enhanced reactivity and selectivity of triazole formation in molecular flasks. A theoretical rationale.

The azide-alkyne cycloaddition assisted by a self-assembled molecular flask developed by Rebek and coworkers (Org. Lett., 2002, 4, 327) has been simulated by means of the ONIOM methodology, thereby evidencing the reliability of this theoretical approach to model such large encapsulated systems. Experimental evidences accounting for this transformation within the supramolecular assembly such as the significant rate enhancement, complete regioselectivity, and product inhibition as the reaction proceeds have been qualitatively disentangled through estimation of the energy barriers and the structural characteristics of the corresponding host-guest complexes.

Assessing the whole range of CuAAC mechanisms by DFT calculations--on the intermediacy of copper acetylides.

The archetypal Cu(I)-catalyzed alkyne-azide click cycloaddition (CuAAC) has been explored thoroughly via density functional calculations, modeling copper nuclei with the LANL2DZ basis set and aqueous environments with CPCM solvation. All the mechanistic proposals, ranging from the intermediacy of copper acetylides to π-complexes and multinuclear clusters have been compared. The known features of the CuAAC reaction such as the observed second order kinetics for the Cu(I) species and the marked regioselectivity have been taken into account. The calculated energy barriers point to the intermediacy of copper(i) acetylides with two metal centers, in agreement with the observed kinetics, which exhibit barriers of 10.1 kcal mol(-1) and 13.7 kcal mol(-1) for the 1,4- and 1,5-regiochemistries, respectively, thus accounting for the marked regioselectivity of the copper catalyzed azide-alkyne cycloaddition. The copper acetylide versus π-complexes dilemma has also been experimentally addressed through the click reaction of benzyl azide and isotopically labeled phenylacetylene. The total proton/deuterium exchange in the afforded triazole demonstrates the formation of a copper acetylide intermediate during the transformation.

A quantitative structure-reactivity relationship in N-acetyl oxazolidines: an electrostatic interaction controls rotamer population.

The conformational population of Z and E isomers of the amide bond in N-acetyl oxazolidines is dictated by the electronic nature of the vicinal aryl ring. Experimental and theoretical data support a rationale based on a strong and stereodirecting charge-charge interaction that should be added to the arsenal of non-covalent interactions and whose influence can be more important than once thought.

La enfermedad del Golfo Pérsico es todavía un enigma para la medicina militar / The Persian Gulf illness is still an enigma for military medicine

El artículo abarca un conjunto seleccionado por los autores de las publicaciones indexadas, que con respecto a eventos de salud relacionados con los veteranos de la Guerra del Golfo Pérsico permitan recopilar nuevas evidencias para una mejor comprensión de esta condición de salud, que en los momentos actuales se considera dentro de la categoría de múltiples síntomas inexplicados (MUS), conjuntamente con la fatiga crónica y la fibromialgia. Lamentablemente, las relaciones de causalidad entre factores diversos que obran en el complejo mundo patogenético y fisiopatológico que constituye la enfermedad del Golfo aún quedan por establecerse de una forma inequívoca. La evidencia clínica aún carece de un sustento repetible y, a medida que envejecen las diversas cohortes de veteranos que participaron en el evento (18 años), lógicamente se superponen hechos biológicos relacionados con el natural deterioro que impone la edad y con los recursos (fondos) para investigaciones muy costosas, que a los países participantes en esto no les interesa destinar

Present paper embrace a set - selected by the authors - of the indexing publications that regarding the health events related to Persian Gulf War veterans allow to collect new evidences for a better comprehension of this health condition, which in nowadays is considered into the category of multiple unexplained symptoms (MUS) together with the chronic fatigue and the bibromyalgia. Lamentably, the causal relations among different factors functioning in the complex pathogenetic and physiopathologic world that is the Persian Gulf illness must to be established in an unequivocal way. The clinical evidence still is lack of a repetitive support, and insofar as the different group of veterans grew old present in this event (18 years), logically there are superimposed biological facts related to the natural deterioration imposed by age and with resources (funds) used in very expensive researches in which the involved countries are not interested

La enfermedad del Golfo Pérsico es todavía un enigma para la medicina militar / The Persian Gulf illness is still an enigma for military medicine

El artículo abarca un conjunto seleccionado por los autores de las publicaciones indexadas, que con respecto a eventos de salud relacionados con los veteranos de la Guerra del Golfo Pérsico permitan recopilar nuevas evidencias para una mejor comprensión de esta condición de salud, que en los momentos actuales se considera dentro de la categoría de múltiples síntomas inexplicados (MUS), conjuntamente con la fatiga crónica y la fibromialgia. Lamentablemente, las relaciones de causalidad entre factores diversos que obran en el complejo mundo patogenético y fisiopatológico que constituye la enfermedad del Golfo aún quedan por establecerse de una forma inequívoca. La evidencia clínica aún carece de un sustento repetible y, a medida que envejecen las diversas cohortes de veteranos que participaron en el evento (18 años), lógicamente se superponen hechos biológicos relacionados con el natural deterioro que impone la edad y con los recursos (fondos) para investigaciones muy costosas, que a los países participantes en esto no les interesa destinar(AU)

Present paper embrace a set - selected by the authors - of the indexing publications that regarding the health events related to Persian Gulf War veterans allow to collect new evidences for a better comprehension of this health condition, which in nowadays is considered into the category of multiple unexplained symptoms (MUS) together with the chronic fatigue and the bibromyalgia. Lamentably, the causal relations among different factors functioning in the complex pathogenetic and physiopathologic world that is the Persian Gulf illness must to be established in an unequivocal way. The clinical evidence still is lack of a repetitive support, and insofar as the different group of veterans grew old present in this event (18 years), logically there are superimposed biological facts related to the natural deterioration imposed by age and with resources (funds) used in very expensive researches in which the involved countries are not interested(AU)

Push-pull 1,3-thiazolium-5-thiolates. Formation via concerted and stepwise pathways, and theoretical evaluation of NLO properties.

The transformation of münchnones (mesoionic rings featuring the 1,3-oxazolium-5-olate core) into their sulfur counterparts (1,3-thiazolium-5-thiolates) by reaction with CS(2), pioneered by Huisgen and his group in the early 1970s, has been re-investigated in detail by means of both experimental and theoretical methods. The synthetic strategy can be tuned to incorporate donor and acceptor groups in appropriate positions. Calculations of molecular hyperpolarizabilities together with orbital topologies evidence that these sulfur-containing heterocycles exhibit nonlinear optical responses, thereby pointing to potential applications of mesoionic structures in the NLO field. From a mechanistic viewpoint, modeling of the whole systems at the B3LYP/6-31G(d) level reveals that concerted and stepwise pathways are operative depending on the substitution pattern of the parent münchnone, which also account for the experimental results.