Luminescent Chiral Furanol-PAHs via Straightforward Ni-Catalysed Csp2 -F Functionalization: Mechanistic Insights into the Scholl Reaction.

Here we report the stepwise synthesis of new nanographenes (NGs) and polycyclic aromatic hydrocarbons (PAHs) obtained via Scholl ring fusion applied at aromatic homologation compounds, which are obtained through one-step Ni-catalysed Csp2 -F functionalization. The latter are rapidly accessed valid precursors for the Scholl reaction, and screening of experimental conditions allowed us to describe for the first time furanol-bearing PAHs. Mechanistic insights are obtained by DFT to rationalize the formation of the furanol PAHs under moderately acidic conditions. All PAHs and NGs synthesized show moderate/weak fluorescent properties, and all PAHs crystallized show some degree of curvature and are obtained as racemic mixtures. Enantiomeric separation by chiral HPLC of one furanol-bearing PAH allowed the study of their chiroptical CD properties.

Gout Screening Identifies a Large Cardiovascular Population at Increased Risk of Mortality.

OBJECTIVE: Gout is prevalent in people with cardiovascular disease, although up to a third of the cases remain unregistered. We aimed to assess whether active gout screening in inpatients with cardiovascular events helps identify patients at higher risk of mortality after discharge. METHODS: This study included patients admitted for cardiovascular events. Gout was established by records review and clinical interview. After discharge, electronic medical records were reviewed for mortality and cause of death. The association between gout and subsequent mortality was tested using Cox regression models. RESULTS: Of 266 recruited patients, 17 were lost to follow-up, leaving a final sample of 249 patients (93.6%). Thirty-six cases (14.5%) were classified as having gout; 13 of these (36.1%) were identified through the interview. Mean follow-up was 19.9 (SD, 8.6) months. Gout significantly increased the risk of all-cause mortality in the overall sample (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.13-3.58) and in the subgroup with a prior diagnosis of gout (HR, 2.89; 95% CI, 1.54-5.41). The adjusted HR for all-cause mortality associated with gout was 1.86 (95% CI, 1.01-3.41). Patients with gout carried an increased risk of both cardiovascular and noncardiovascular deaths; age and chronic kidney disease were mortality predictors within the gout population. CONCLUSION: Gout was an independent predictor of subsequent all-cause mortality in patients admitted for cardiovascular events. Active screening for gout allowed the detection of a larger population at high risk of mortality and could help tailor patient management to minimize the cardiovascular impact.

Successive Diels-Alder Cycloadditions of Cyclopentadiene to [10]CPP⊃C60: A Computational Study.

Fullerenes have potential applications in many fields. To reach their full potential, fullerenes have to be functionalized. One of the most common reactions used to functionalize fullerenes is the Diels-Alder cycloaddition. In this case, it is important to control the regioselectivity of the cycloaddition during the formation of higher adducts. In C60, successive Diels-Alder cycloadditions lead to the Th-symmetric hexakisadduct. In this work, we explore computationally using density functional theory (DFT) how the presence of a [10]cycloparaphenylene ring encapsulating C60 ([10]CPP⊃C60) affects the regioselectivity of multiple additions to C60. Our results show that the presence of the [10]CPP ring changes the preferred sites of cycloaddition compared to free C60 and leads to the formation of the tetrakisadduct. Somewhat surprisingly, our calculations predict formation of this particular tetrakisadduct to be more favored in [10]CPP⊃C60 than in free C60.

Resonance-Assisted Hydrogen Bond-Revisiting the Original Concept in the Context of Its Criticism in the Literature.

In the presented research, we address the original concept of resonance-assisted hydrogen bonding (RAHB) by means of the many-body interaction approach and electron density delocalization analysis. The investigated molecular patterns of RAHBs are open chains consisting of two to six molecules in which the intermolecular hydrogen bond stabilizes the complex. Non-RAHB counterparts are considered to be reference systems. The results show the influence of the neighbour monomers on the unsaturated chains in terms of the many-body interaction energy contribution. Exploring the relation between the energy parameters and the growing number of molecules in the chain, we give an explicit extrapolation of the interaction energy and its components in the infinite chain. Electron delocalization within chain motifs has been analysed from three different points of view: three-body delocalization between C=C-C, two-body hydrogen bond delocalization indices and also between fragments (monomers). A many-body contribution to the interaction energy as well as electron density helps to establish the assistance of resonance in the strength of hydrogen bonds upon the formation of the present molecular chains. The direct relation between interaction energy and delocalization supports the original concept, and refutes some of the criticisms of the RAHB idea.

Tuning the Strength of the Resonance-Assisted Hydrogen Bond in Acenes and Phenacenes with Two o-Hydroxyaldehyde Groups-The Importance of Topology.

The fact that intramolecular resonance-assisted hydrogen bonds (RAHBs) are stronger than conventional ones is attributed to the partial delocalization of the π-electrons within the hydrogen bond (HB) motif, the so-called quasi-ring. If an aromatic ring is involved in the formation of the RAHB, previous studies have shown that there is an interplay between aromaticity and HB strength. Moreover, in 1,3-dihydroxyaryl-2-aldehydes, some of us found that the position of the quasi-ring formed by the substituents interacting through RAHB influences the strength of the H bonding, the HBs being stronger when a kinked-like structure is generated by formation of the quasi-ring. In this work, we explore this concept further by considering a set of acenes and phenacenes of different sizes with two o-hydroxyaldehyde substituents. Calculations with the CAM-B3LYP/6-311++G(d,p) + GD3B method show that for long acenes or phenacenes, once the substituent effect loses importance because quasi-rings are pulled apart far from each other, the different topologies rule the HB distances. This fact can be explained in most cases using an extended Clar's aromatic π-sextet model. In some kinked systems, however, the justification from the Clar model has to be complemented by taking into account the repulsion between hydrogen atoms. Triphenylene-like compounds with different numbers of benzene rings have been studied, finding out a very good relationship between aromaticity of the ipso- and quasi-rings with the RAHB distances. This result confirms the importance of the communication of the π-systems of the ipso- and quasi-rings.

Tuning the Strength of the Resonance-Assisted Hydrogen Bond in o-Hydroxybenzaldehyde by Substitution in the Aromatic Ring1.

Intramolecular resonance-assisted hydrogen bonds (RAHBs) are stronger than conventional hydrogen bonds (HBs) thanks to the extra stabilization connected with the partial delocalization of the π-electrons within the HB motif containing conjugated formally single and double bonds. When these conjugated bonds are part of an aromatic ring, there is an interplay between resonance-assisted hydrogen bonding and the aromaticity of the ring. The main aim of the present work is to analyze the changes in RAHB strength by substitution in the aromatic ring. For this purpose, we use density functional theory methods to study all possible mono- and disubstitutions in the four free positions of the aromatic ring of o-hydroxybenzaldehyde. As substituents, we consider three π-electron donating groups (EDG: NH2, OH, and F) and three π-electron withdrawing groups (EWG: NO2, NO, and CN). We show that it is possible to tune the HB bond distance in the RAHB by locating different substituents in given positions of the aromatic ring. Indeed, certain combinations of EDG and EWD result in a reduction or increase of the HB distance by up to 0.05 Å. Results found can be explained by considering the existence of a resonance effect of the π-electrons within the HB motif.

The Role of Aromaticity, Hybridization, Electrostatics, and Covalency in Resonance-Assisted Hydrogen Bonds of Adenine-Thymine (AT) Base Pairs and Their Mimics.

Invited for this issues cover are Dr. Célia Fonseca Guerra from the VU University of Amsterdam and her collaborators at the University of Girona. The cover picture shows H-bonds in the adenine-thymine Watson-Crick base pair. An essential part of these H-bonds is their covalent component arising from donor-acceptor interactions between N or O lone pairs and the N-H antibonding σ* acceptor orbital. This charge-transfer interaction is represented by green figures walking on the pedestrian crossing, connecting the bases. This covalent component is the reason why H-bonds between DNA and/or unsaturated model bases are significantly stronger than those between analogous saturated bases. This contrasts sharply with the classical picture of predominantly electrostatic H-bonds which is not only incomplete in terms of a proper bonding mechanism, but also fails to explain the trend in stability. For more details, see the Full Paper on p. 318 ff.

Electron transfer from aromatic amino acids to guanine and adenine radical cations in pi stacked and T-shaped complexes.

Similar redox properties of the natural nucleobases and aromatic amino acids make it possible for electron transfer (ET) to occur between these sites in protein-nucleic acid complexes. Using DFT calculations, we estimate the ET rate from aromatic amino acid X (X = Phe, His, Tyr and Trp) to radical cations of guanine (G) and adenine (A) in dimers G-X and A-X with different arrangement of the subunits. We show that irrespective of the mutual orientation of the aromatic rings, the electronic interaction in the systems is strong enough to ensure effective ET from X to G(+) or A(+). Surprisingly, relatively high ET rates are found in T-shaped dimers. This suggests that pi stacking of nucleobases and aromatic amino acids is not required for feasible ET. In most complexes [G-X](+) and [A-X](+), we find the excess charge to be confined to a single site, either the nucleobase or amino acid X. Then, conformational changes may initiate migration of the radical cation state from the nucleobase to X and back. The ET process from Trp and Tyr to G(+) is found to be faster than deprotonation of G(+). Because the last reaction may lead to the formation of highly mutagenic species, the efficient repair of G(+) may play an important role in the protection of genomic DNA from oxidative damage.

Dihydrogen bonding: donor-acceptor bonding (AH...HX) versus the H2 molecule (A-H2-X).

Dihydrogen bonds (DHBs) play a role in, among others, crystal packing, organometallic reaction mechanisms, and potential hydrogen-storage materials. In this work we have analyzed the central H-H bond in linear H(4), LiH...HX, BH(4)(-)...HX, and AlH(4)(-)...HX complexes with various X by using the quantitative molecular orbital model contained in Kohn-Sham density functional theory at the BP86/TZ2P level of theory. First, we address the questions of if and how one can distinguish, in principle, between a H...H donor-acceptor DHB and the formation of an H(2) molecule by using the simple H(4) model system. The results of these analyses have been used to gain an understanding of the bonding in more realistic model systems (some of which have been studied experimentally), and how this differs from the bonding in H(4).

Interplay between intramolecular resonance-assisted hydrogen bonding and local aromaticity. II. 1,3-Dihydroxyaryl-2-aldehydes.

The interplay between aromaticity and hydrogen bonding in 1,3-dihydroxyaryl-2-aldehydes is investigated by means of quantum-chemical calculations. The position of the extra ring formed by substituents interacting through the hydrogen bond (HB) is found to influence both the strength of the HB and the local aromaticity of the polycyclic aromatic hydrocarbon (PAH) skeleton. The HBs are stronger and the entire system is energetically more stable when a kinked-like structure is generated by formation of the quasi-ring. Relatively greater loss of aromaticity of the ipso-ring can be observed for these kinked-like structures because of the larger participation of pi-electrons coming from the ipso-ring in the formation of the quasi-ring. We conclude that the quasi-ring partially adopts the role of a typical aromatic ring, the position of which has a meaningful influence on the aromaticity of the rest of the rings. This makes it possible to explain and modify the properties of 1,3-dihydroxyaryl-2-aldehydes by the planned substitution to the appropriate position of the given PAH.

Ten-year experience with acenocoumarol treatment in an ambulatory cohort of Spanish patients.

OBJECTIVE: To analyse incidence of hemorrhagic and thrombotic events in a series of ambulatory patients receiving acenocoumarol in a rural area of Spain (1997-2007). RESULTS: Out of 1,544 patients, 1,086 are receiving acenocoumarol at present (2% of our region's population). The total follow-up was 5,462 patients-years. Median age was 74 years. INR therapeutic range was 2.0-3.0 in 82.5%. Atrial fibrillation (AF) was the most frequent indication (73%). Incidence of hemorrhagic and thrombotic events was 2.27 and 0.2/100 patients-year, respectively. Gastrointestinal tract was the most frequent site of bleeding. In multivariate analysis, patients with AF and prosthetic heart valves (PHV) had increased risk of bleeding (OR 2.1 and 4.8, respectively). Age and therapeutic ranges of INR were not associated with increased risk of bleeding. CONCLUSIONS: 2% of our population is receiving acenocoumarol. Incidence of hemorrhagic and thrombotic events was low. Patients with AF and PHV had increased risk of bleeding.

[Organizing pneumonia associated with the use of pegylated interferon alfa]. / Neumonía organizada asociada a tratamiento con peginterferón alfa.

Organizing pneumonia is a well-differentiated clinical and histologic entity whose onset is usually subacute with respiratory symptoms and pulmonary infiltrates. Its origin may be unknown (cryptogenic) or it may be associated with various medical conditions, infectious diseases, or drugs. Diagnosis is confirmed by the presence of foci of organizing pneumonia in lung biopsy specimens. Our patient was a 49-year-old man infected with the hepatitis C virus who was receiving pegylated interferon alfa-2b. He presented with dry cough, fever, dyspnea, and ground glass pulmonary infiltrates. After an open lung biopsy, he was diagnosed with organizing pneumonia. When pegylated interferon was discontinued and corticosteroids started, the symptoms and pulmonary infiltrates disappeared. To our knowledge, this is the second report of organizing pneumonia related to pegylated interferon alfa-2b.

Electron density topological properties are useful to assess the difference between hydrogen and dihydrogen complexes.

B3LYP/6-31++G(d,p) and MP2/6-31++G(d,p) calculations for a series of hydrogen- and dihydrogen-bonded systems have been carried out in order to analyze the topology of the electron density and the energy densities at the respective energy-optimized bond critical points. Even though there are no significant differences when these properties are represented as a function of the dimerization energy, they can be separated into two well-defined sets if those properties are correlated with intermolecular distances. When analyzing the dependence of various properties with equilibrium bond lengths, the specific trends of dihydrogen bond systems consist of (a) lower electron density at the bond critical point, and (b) lower concentration/depletion of that density which can be translated in a different behavior for the Laplacian components. Furthermore, the sets of molecules form two different plots which allow for a valuable classification between hydrogen- and dihydrogen-bonded systems.

Influence of the Side Chain in the Structure and Fragmentation of Amino Acids Radical Cations.

The conformational properties of ionized amino acids (Gly, Ala, Ser, Cys, Asp, Gln, Phe, Tyr, and His) have been theoretically analyzed using the hybrid B3LYP and the hybrid-meta MPWB1K functionals as well as with the post-Hartree Fock CCSD(T) level of theory. As a general trend, ionization is mainly localized at the -NH2 group, which becomes more planar and acidic, the intramolecular hydrogen bond in which -NH2 acts as proton donor being strengthened upon ionization. For this reason, the so-called conformer IV(+) becomes the most stable for nonaromatic amino acid radical cations. Aromatic amino acids do not follow this trend because ionization takes place mainly at the side chain. For these amino acids for which ionization of the side chain prevails over the -NH2 group, structures III(+) and II(+) become competitive. The Cα-X fragmentations of the ionized systems have also been studied. Among the different decompositions considered, the one that leads to the loss of COOH(•) is the most favorable one. Nevertheless, for aromatic amino acids fragmentations leading to R(•) or R(+) start being competitive. In fact, for His and Tyr, results indicate that the fragmentation leading to R(+) is the most favorable process.

Interplay between intramolecular resonance-assisted hydrogen bonding and aromaticity in o-hydroxyaryl aldehydes.

In this work, we analyze a series of o-hydroxyaryl aldehydes to discuss the interrelation between the resonance-assisted hydrogen bond (RAHB) formation and the aromaticity of the adjacent aromatic rings. As compared to the nonaromatic reference species (malonaldehyde), the studied compounds can be separated into two groups: first, the set of systems that have a stronger RAHB than that of the reference species, for which there is a Kekulé structure with a localized double CC bond linking substituted carbon atoms; and second, the systems having a weaker RAHB than that of the reference species, for which only pi-electrons coming from a localized Clar pi-sextet can be involved in the RAHB. As to aromaticity, there is a clear reduction of aromaticity in the substituted ipso ring for the former group of systems due to the formation of the RAHB, while for the latter group of species only a slight change of local aromaticity is observed in the substituted ipso ring.