Stereoisomer Discrimination in Complexes of Halogen-Substituted Difuranes and Li or Na Cations

The theoretical study of the stereoisomer discrimination of the 2:1 homo- and heterochiral complexes between chiral 5,5‘-dihalogen bifuranes and lithium or sodium cations has been carried out using DFT methods. To understand the chiral effect produced by the introduction of a second bifurane molecule, the 1:1 complexes also have been calculated. All the 2:1 heterochiral complexes computed showed a nonplanar configuration around the metallic cation, but in the case of the homochiral complexes, the dibromo− and dichloro−bifurane systems around Na+ were quasi-planar. The nature of the interactions established between cations and bifurane systems has been analyzed by means of AIM and NBO, and correlations between the electron density topological parameters with the O···M distance and with the orbital interaction energy have been found. Stereodiscrimination is observed favoring the heterochiral complexes except for the Na+ complexes with chloro and bromo substituents in which the homochiral forms are more stable. Stereodiscrimination values correlate with the difference in electron density at the bond critical point and orbital interaction energy between homo- and heterochiral systems

An Attractive Interaction between the π-Cloud of C₆F₆ and Electron-Donor Atoms

A theoretical study of the possible interaction of the π-cloud of hexafluorobenzene (C6F6) with several small electron-donor molecules (FH, HLi, :CH2, NCH, and CNH) has been carried out. The calculations have been performed using HF, MP2, and hybrid HF/DFT methods (B3LYP) with the 6-31G** and 6-311++G** basis sets. The topology of the electron density of the complexes has been characterized using the AIM methodology. The characteristics of the electron density and molecular electrostatic potential maps of benzene and hexafluorobenzene have been compared. Finally, the results obtained from a search in the Cambridge Structural Database system of this kind of interaction are shown

Interaction of Anions with Perfluoro Aromatic Compounds

The complexes formed by a variety of anions with perfluoro derivatives of benzene, naphthalene, pyridine, thiophene, and furan have been calculated using DFT (B3LYP/6-31++G**) and MP2 (MP2/6-31++G** and MP2/6-311++G**) ab initio methods. The minimum structures show the anion interacting with the π-cloud of the aromatic compounds. The interaction energies obtained range between −8 and −19 kcal mol-1. The results obtained at the MP2/6-31++G** and MP2/6-311++G** levels are similar. However, the B3LYP/6-31++G** results provide longer interaction distances and smaller interaction energies than do the MP2 results. The interaction energies have been partitioned using an electrostatic, polarization, and van der Waals scheme. The AIM analysis of the electron density shows a variety of topologies depending on the aromatic system considered

Behavior of Ylides Containing N, O, and C Atoms as Hydrogen Bond Acceptors

The hydrogen bond (HB) basicity of a series of ylides containing nitrogen, oxygen, or carbon as heavy atoms, as well as the influence of the formation of the HB complexes on their structure, has been studied. In addition, in this paper we propose the formation of some rather strong HBs (that could be considered low-barrier hydrogen bonds, LBHBs) between ylides and different neutral molecules. The ylides chosen for the study were H3N+−N-H, Me3N+−N-H, H2O+−N-H, Me2O+−N-H, H2O+−O-, Me2O+−O-, and Me3N+−C-H2. As HB donors, classical donors such as HF, HCN, and HCCH were used. The analysis of the protonation energies of the ylides and the optimized geometries, interaction energies, and characteristics of the electron density of the complexes shows that these ylides are very good HB acceptors, forming stable complexes even with weak HB donors. With strong donors, when the proton transfer did not take place, very strong HBs were formed with quite large interaction energies and very short HB distances which could be considered as LBHBs. Moreover, we have found that the sign of the Laplacian of the electron density at the bond critical point (∇2ρBCP) and that of the energy density (HBCP) could characterize the strength of HBs. Thus, weak HBs (EI < 12.0 kcal/mol) show both ∇2ρBCP and HBCP > 0, and medium HBs (12.0 EI 2ρBCP > 0 and HBCP EI > 24.0 kcal/mol) show both ∇2ρBCP and HBCP < 0

Study of Meldrum’s Acid Cyclization Reactions

On the basis of the cyclization reactions reported by Danishefsky et al. of Meldrum’s acid hydroxylethyl and anilinoethyl derivatives, the cyclization of the sulfamidomethylene and ureidomethylene derivatives was attempted without success. To understand the lack of reactivity of these compounds versus the successful cyclization of the ethyl derivatives, the corresponding mechanisms of reaction for both processes have been explored by means of MP2/6-311+G­(d,p) calculations in an aqueous environment. The conformational analysis of all of these structures revealed that, while for the ethyl derivatives the minimum energy conformation corresponds to that of the cyclization initiating structure, for the methylene analogues the entrance channel conformations are substantially less stable than the energy minimum. Intramolecular hydrogen bonds were found in all of the energy minima as well as in the cyclization initiating conformations as determined by analysis of their electron density. The potential energy surfaces for the successful and unsuccessful cyclization processes were obtained at room temperature and 100 °C. Comparison of both processes allows rationalization that the lack of reactivity of the methylene derivatives can be thermodynamically explained based not only on the strength of the intramolecular hydrogen bond formed in their energy minima but also by the energy penalty needed to reach the entrance channel conformation and by the calculated energy barriers

Aminoalkyl Derivatives of Guanidine Diaromatic Minor Groove Binders with Antiprotozoal Activity

Considering the strong DNA minor groove binding observed for our previous series of diaromatic symmetric and asymmetric guanidinium and 2-aminoimidazolinium derivatives, we report now the synthesis of new aminoalkyl derivatives of diaromatic guanidines with potential as DNA minor groove binders and antiprotozoal activity. The preparation of these aminoalkyl derivatives (<b>12a</b>–<b>e</b>, <b>13a</b>–<b>e</b>, <b>14a</b>–<b>c</b>,<b>e</b>, <b>15a</b>–<b>e</b>, <b>16a</b>–<b>e</b>) is presented as well as their affinity for DNA which was evaluated by means of DNA thermal denaturation experiments. Finally, the antiprotozoal activity of most of these aminoalkyl minor groove binders was evaluated in vitro against <i>Trypanosoma brucei rhodesiense</i> (8 compounds) and <i>Plasmodium falciparum</i> (18 compounds). The O-linked derivatives <b>13c</b> and <b>14c</b> showed 100 nM activities against <i>P. falciparum,</i> whereas for <i>T. b. rhodesiense</i> all compounds tested showed micromolar activity. Some of the derivatives prepared seem to exert the antimalarial activity by binding to the DNA minor groove whereas other sets of compounds could exert this antimalarial activity by inhibiting the parasite dihydrofolate reductase, for example

Aromatic Bis‑<i>N</i>‑hydroxyguanidinium Derivatives: Synthesis, Biophysical, and Biochemical Evaluations

In this paper we report the synthesis of a new family of hydroxyguanidinium aromatic derivatives (4a–g) as potential minor groove binders and cytotoxic agents. Their DNA affinity was evaluated by thermal denaturation experiments using salmon sperm DNA. The antiproliferative effects of derivatives 4a, 4d, and 4f were evaluated in human promyelocytic HL-60, breast carcinoma MCF-7, and neuroblastoma Kelly cell lines using the AlamarBlue viability assay, and IC50 values were obtained. All three compounds were active in the HL-60 cell line. In particular, 4b exhibits antiproliferative effects in all three cell lines while 4d reduced HL-60 and Kelly viability. Both 4b and 4d produced considerable antiproliferative activity in the Kelly cell line. Derivative 4d was chosen for further cell cycle and apoptosis studies using flow cytometric analysis of cellular DNA content

Computational Study-Led Organocatalyst Design: A Novel, Highly Active Urea-Based Catalyst for Addition Reactions to Epoxides

An in silico study examined the stabilities of hydrogen-bonded complexes between simple thiourea catalysts and three different electrophiles and identified a novel, highly active N-tosyl urea catalyst for the promotion of addition reactions to epoxide electrophiles. Synthesis and evaluation of 6 revealed it to be a powerful catalyst for the addition of 1,2-dimethylindole to styrene oxide under conditions in which simple N,N-bis-aryl ureas and thioureas (including 1) are inactive. Subsequent studies determined 6 to be compatible with a range of indole and epoxide substrates (including (E)-stilbene oxide) and found that relatively poor nucleophiles such as sterically and electronically deactivated anilines, thiophenol, and benzyl alcohol could be efficiently and regioselectively added to oxiranes under mild conditions

Guanidine Complexes of Platinum: A Theoretical Study

We have studied theoretically the complexes of model <i>N</i>-phenylguanidine/ium derivatives with PtCl₃^– and PtCl₂ in different coordinating modes (mono- and bidentate) with different N atoms of the guanidine/ium moiety using the B3LYP/6-31+G** and LANL2DZ mixed basis set. This will aid the understanding of the complexation between platinum and the guanidine or guanidinium moiety in order to design dual anticancer agents that combine a guanidine-based DNA minor groove binder and a cisplatin-like moiety. Calculated interaction and relative energies, analysis of the electron density, and examination of the orbital interactions indicate that the most stable type of complex is that with a monodentate interaction between PtCl₃^– and guanidinium established through one of the NH₂ groups. Next, we optimized the structure of three <i>bis</i>-guanidinium diaromatic systems developed in our group as DNA minor groove binders and their complexation with PtCl₃^–, finding that the formation of Pt complexes of these minor groove binders is favorable and would produce stable monodentate coordinated systems

High DNA Affinity of a Series of Peptide Linked Diaromatic Guanidinium-like Derivatives

In this paper we report the design and synthesis of a new family of asymmetric peptide linked diaromatic dications as potent DNA minor groove binders. These peptide-linked compounds, with a linear core, displayed a much larger affinity than other guanidinium-like derivatives from the same series with curved cores. As a first screening, the DNA affinity of these structures was evaluated by means of thermal denaturation experiments, finding that the nature of the cation (guanidinium vs 2-aminoimidazolinium) significantly influenced the binding strength. Their binding affinity was assessed by implementing further biophysical measurements such as surface plasmon resonance and circular dichroism. In particular, it was observed that compounds <b>6</b>, <b>7</b>, and <b>8</b> displayed both a strong binding affinity and significant selectivity for AT oligonucleotides. In addition, the thermodynamics of their binding was evaluated using isothermal titration calorimetry, indicating that the binding is derived from favorable enthalpic and entropic contributions