Interactions between cations and aromatic molecules can be often find on a large number of biomolecular systems, such as proteins and receptor-ligand complexes. In addition, its important role in biological processes such as molecular recognition, drug action, and protein folding has been revealed by extensive experimental and theoretical investigations. Most previous theoretical investigations of cation···p interactions, have been focused on their characteristics in the gas phase, with less attention to their behavior in aqueous environment. In this latter case, most of the work has been focused on the whole effect of water solution as a medium on the cation···p interactions. Hence, it is important studying the influence of individual water molecules on the interaction as the cation···p complex is sequentially hydrated. The ammonium···phenol and methylammonium···phenol cation···p complex was selected as a model system to explore how water molecules affect the cation···p interaction. To mimic the process of water molecules binding to a cation···p complex, water molecules were introduced into the complex one by one. The purpose of this study is studying the geometrical characteristic of cation···p complexes with different numbers of water molecules and to investigate how the binding of water molecules to an existing cation···p complex affects the cation···p interaction.

Among the different forces observed in biological complexes, the cation···p interaction is a strong, non-covalent binding force which participates in a wide variety of processes such as molecular recognition in biological receptors, enzymatic catalysis, etc. The nature and characteristics of this kind of interaction has been mainly theoretically studied in the gas phase, despite being known that the presence of water molecules modulates the strength of the interaction between metal ions and aromatic species. Besides, most studies have employed benzene as a prototype of aromatic unit. On the other hand, an also simple aromatic system as phenol presents two coordination sites for cations: the aromatic ring and the hydroxyl oxygen, thus allowing a greater variety of structures to be formed than in benzene. The hydroxyl group can also be hydrated and participate in the formation of the hydrogen bond network. In the present work, a study of the interaction between cations and phenol has been carried out to shed light on the effect of successive hydration on the interaction. So, ab initio and DFT methods were employed for studying the stepwise microhydration of phenol···cation complexes, locating the most stable structures and obtaining the corresponding complexation energies. The results suggest that the participation of the hydroxyl group is already relevant in clusters containing a small number of water molecules.

Neurodegenerative diseases are becoming prevalent pathologies in developed societies due to increasing average of life expectancy of the population. This fact has encouraged an active research in the development of new drugs, since they may represent an important advance in the treatment of complex diseases such as Alzheimer and Parkinson\'s diseases. Coumarins are a large family of compounds, of both natural and synthetic origin, important because of the pharmacological activities that this compounds display. Therefore, they occupy an important place in the organic and medicinal chemistry realm. In recent years, coumarins have been attracting interest because of their ability of inhibiting some enzymes. The versatility of the Perkin and Knoevenagel reactions has led to a large family of differently substituted compounds. In order to find the structural features for the human MAO inhibitory activity and selectivity, in the present communication we report the synthesis, pharmacological evaluation and a comparative study of a new series of 3-phenylcoumarins versus 3-benzoylcoumarins. A bromo atom and a methoxy/hydroxy substituent were introduced in these scaffolds at different positions of the coumarin moiety. The synthesized compounds were evaluated as MAO-A and B inhibitors using R-(-)-deprenyl and iproniazide as reference compounds. The presence or absence of a carbonyl group between the coumarin and the phenyl substituent in 3 position remarks, respectively, the MAO-A or MAO-B inhibitory activity. Some of the new compounds showed MAO-B inhibitory activities in the low nanomolar range. Compound 2 (IC₅₀ = 1.35 nM) showed higher inhibitory activity than the R-(-)-deprenyl (IC₅₀ = 19.60 nM) and higher MAO-B selectivity, with more than 74,074-fold inhibition level, respecting to the MAO-A isoform. In addition, docking experiments were carried out on hMAO-A and h-MAO-B structures. This study has provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of this coumarin scaffolds.

2,2\'-Dicarbazole-1,1\'-diphenyl (2,2\'-CBP) is a prospective host material for phosphorescent light emmiting diodes (PHOLED)s. The synthesis of 2,2\'-CBP is limited by the availability of starting materials. We wish to report an efficient protocol for the synthesis of 2,2\'-CBP with overal yield about 90% starting from o-nitrobenzoic acid. Thus, Pd catalized homocoupling of o-nitrobenzoic acid affords 2,2\'-dinitro-1,1\'-diphenyl (2,2\'-DNDP) in 95% yield. Pd catalized reduction of 2,2\'-DNDP and the following double arylation of 2,2\'-diaminodiphenyl with 2,2\'-dibromo-1,1\'-diphenyl (which can be obtained from 2,2\'-diamino-1,1\'-diphenyl in 70-76% yield) affords the final product in 95% yield with overal yield after 3 steps of 90 %.

Despite being intense in the gas phase, the strength of the interaction between a cation and an aromatic cloud decreases significantly when solvated. This effect has an important impact on a variety of systems where the cation•••pi interaction is known to play a key role. In the case of cation•••pi contacts involving aromatic amino acid residues, the degree of exposure to the solvent can be widely variable, so the interaction can be modulated by the environment in an almost continuous way. Most theoretical studies regarding cation•••amino acid interactions have been performed by considering simple alkaline cations in the gas phase. However, interactions can also be established with more complex cations from other amino acids, such as it is the case with arginine cationic side chain and the aromatic units in phenylalanine, tyrosine and tryptophan. In the present work ab initio and DFT methods were employed to study complexes formed by phenylalanine and a guanidinium cation representing the cationic chain of arginine. The results help understanding the impact of the interaction on the structure of phenylalanine, and constitute a first step towards the study of the effects caused by water molecules in the characteristics of these systems.

We have recently reported an experimental and computational study on [1,5]-H shifts in acetal-ketenimines and acetal-carbodiimides in which the acetalic H atom migrates to the central electrophilic carbon atom of the heterocumulenic fragment. These rearrangements occur under unusual mild thermal conditions, and were chemically interpreted as hydride shifts. The resulting intermediates undergo 6π electrocyclic ring closure to give, respectively, quinoline and quinazoline rings. As a continuation we considered the replacement of the ketenimine and carbodiimide functions by cumulene fragments. As expected, the thermal treatment of several acetal-allenes led to 1,2-dihydronaphthalenes by a similar [1,5]-H/6π electrocyclic ring closure tandem process. Next, as we will describe in this communication, we essayed the cyclization of acetal and dithioacetal-allenes, by activating the electron-rich cumulene function with a protic acids Surprisingly, these reactions provided new heterocyclic fused indenes as reaction products. A mechanistic rationale for explaining these results will be also disclosed.

Recently we have observed accelerating influence of trimethyl silyl chloride addition on the rate of the reactions of 5-(α-amino- α\'-hydroxy)methylene Meldrum\'s Acids with amines particularly in the case of highly basic amines. However the nature of the aforementioned process remain unexplained. In proposed communication we wish to report insightful elucidation of this mechanism. The reaction under investigation involves simply addition of the trimethyl silyl chloride to the mixture of amine and carbamoyl Meldrum\'s acid derivative. We considered three potentially possible ways for the TMSCl action. The first possibility is formation of the O-silylated Meldrum acid, which would exclude formation of salt Meldrum\'s acid with amine, what undoubtedly hindered this reaction. The next way for the acceleration of the process is silylation of amine and subsequent reaction of silylated amine with carbamoyl Meldrum\'s acid. The last possibility is connected with the formation of equimolar amount of HCl during the reaction of TMSCl with carbamoyl Meldrum\'s acid or amine which should speed up the rate of decomposition of the Meldrum\'s acid derivative. The NMR monitored experiments as well classical experiments in which predicted intermediated were added to the reaction mixtures excluded formation of O-silylated Meldrum\'s acid as well as influence of formed HCl as a reason of the acceleration investigated reaction. Our experiments revealed that silylated amine is responsible for rate acceleration of the reaction amines and 5-(α-amino- α\'-hydroxy)methylene Meldrum\'s Acids in the presence of TMSCl.

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used against the human immunodeficiency virus type-1 (HIV-1), mostly to prevent mother-to-child HIV transmission in developing countries [1]. One of the limitations of NVP use is severe hepatotoxicity [2], which raises concerns about its chronic administration, particularly in the perinatal and pediatric settings. The reasons for the adverse effects of NVP administration are currently not clear, although there is increasing evidence that metabolic activation to reactive electrophiles capable of reacting with bionucleophiles is likely to be involved in the initiation of toxic responses. Phase I NVP metabolism involves oxidation of the 4-methyl substituent to 12-hydroxy-NVP , and the formation of phenolic derivatives that are conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species prone to react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As part of a program aimed at evaluating the possible contribution of quinoid derivatives of NVP Phase I phenolic metabolites to the toxic responses elicited by the parent drug, we have investigated the oxidation of 2-hydroxy-NVP with dipotassium nitroso-disulfonate (Frémy\'s salt), mimicking the one-electron oxidation involved in enzyme-mediated metabolic oxidations. We report herein the isolation and full structural characterization (by NMR, MS and X-ray diffraction) of a 1H-pyrrole-2,5-dione derivative as a major product, stemming from an unusual pyridine ring contraction. References: [1] Lockman et al., N. Engl. J. Med. 2007, 356, 135-147. [2] Pollard et al., Clin. Ther 1998, 20, 1071–1092. Acknowledgments: We thank the Portuguese NMR Network (IST-UTL Center) and the Portuguese MS Network (IST-UTL Center) for providing access to the facilities. This work was supported in part by research

We have explored the reaction of substituted alkenylaluminums that were prepared by various methods with sulfonyl halides, which we believed to be effective sources of electrophilic halogen. Alkenylaluminums obtained in Zr-catalyzed methylalumination of terminal alkynes react with sulfonyl chlorides and bromides to give corresponding alkenyl halides in high yield. Cycloalumination of 1-decyne and phenylacetylene affords aluminacyclopent-2-enes, which react with 1 equivalent of sulfonyl chlorides and bromides to give after deuterolysis alkenyl halides in high yield. The halogenation proceeds regioselectively only at the sp²-hybridized carbon atom and with the retention of the configuration of the double bond. To our surprise, b-substituted vinylaluminums that were obtained by hydroalumination of terminal alkynes (1-octyne, phenylacetylene) by DIBAL-H do not react with sulfonyl halides (MsCl, TsCl, MsBr). Thus, the sulfonyl chlorides and bromides are more convenient halogenation agents for b,b- and a,b,b-substituted vinylaluminums that were prepared by Zr-catalyzed methylalumination and cycloalumination compared to NCS and NBS, which is manifested in the facts that: a) the reaction proceeds at room temperature; b) the reaction does not require the use of ether solvent (moreover, the latter inhibits the halogenation), c) higher regioselectivity for the bromination of aluminacyclopent-2-enes is observed.

N-Tosyl-2-nitropirrole and N-Tosyl-3-nitropirrole reacts with poorly and activated dienes using protic ionic liquids as reaction media. They exhibit a dienophile character producing the corresponding indoles through a Diels-Alder process. In all cases the presence of protic ionic liquids as reaction media improve the yields respect to use of molecular solvent, while the temperature and the reaction time decrease.