Synthesis of 2,24-Diene-12,13,15,16,34,35,37,38-octaphenyl[4.4]-triphenylparacyclophane.

A new octaphenyl[4.4]triphenylparacyclophanediene was readily synthesized in six steps from p-xylene via the installment of bromine atoms, replacement with a vinyl group, carbonylative coupling, intermolecular followed by intramolecular double Grubbs olefin metathesis, Knoevenagel condensation, and Diels-Alder cycloaddition. The belt-shaped structure and trans-stereochemistry of the alkene moieties of the octaphenyl[4.4]triphenylparacyclophane and a synthetic intermediate, 2,21-dioxo-11,30-diene[3.4.3.4]paracyclophane, were determined by X-ray crystallography. The synthetic methodology leading to octaphenyl[4.4]triphenylparacyclophane is applicable for the synthesis of substituted triphenylparacyclophanes and possibly their corresponding bis-hexabenzocoronenylparacyclophanes via a Scholl-Mullen oxidative aryl-aryl coupling reaction.

Modulating the physical properties of solid forms of urea using co-crystallization technology.

The solid-form landscape of urea was explored using full interaction maps (FIMs) and data from the CSD to develop optimum protocols for synthesizing co-crystals of urea. As a result, 49 of the 60 attempted reactions produced new co-crystals, and the crystal structures of four of these are presented. Moreover, the goal of reducing the solubility and lowering the hygroscopicity of the parent compound was achieved, which in turn offers new opportunities for application as a slow-release fertilizer with limited hygroscopicity, thereby reducing many current problems of transport, handling, and storage of urea.

Crystal structure of {(R)-N2-[(benzo[h]quinolin-2-yl)meth-yl]-N2'-[(benzo[h]quinolin-2-yl)methyl-idene]-1,1'-binaphthyl-2,2'-di-amine-κ4N,N',N'',N'''}(trifluoromethane-sulfonato-κO)zinc(II)} trifluoromethane-sulfonate di-chloro-methane 1.5-solvate.

The zinc(II) atom in the title compound, [Zn(C48H31N4)(CF3SO3)](CF3SO3)·1.5CH2Cl2, adopts a distorted five-coordinate square-pyramidal geometry. It is coordinated by one tri-fluoro-methane-sulfonate ligand and four N atoms of the N2-[(benzo[h]quinolin-2-yl)meth-yl]-N2'-[(benzo[h]quinolin-2-yl)methyl-idene]-1,1'-binaphthyl-2,2'-di-amine ligand. The complex is present as a single-stranded P-helimer monohelical structure incorporating π-π and/or σ-π inter-actions. One of the imine bonds present in the original ligand framework is reduced, leading to variations in bond lengths and torsion angles for each side of the ligand motif. The imine-bond reduction also affects the bond lengths involving the metal atom with the N-donor atoms located on the imine bond. There are two mol-ecules of the complex in the asymmetric unit. One of the mol-ecules exhibits positional disorder within the coordinating tri-fluoro-methane-sulfonate ion making the mol-ecules symmetric-ally non-equivalent.

Crystal structure of ({(1R,2R)-N,N'-bis-[(quino-lin-2-yl)methyl]cyclo-hexane-1,2-di-amine}-chlorido-iron(III))-µ-oxido-[tri-chlorido-ferrate(III)] chloro-form monosolvate.

The first FeIII atom in the solvated title compound, [Fe2Cl4O(C26H28N4)]·CHCl3, adopts a distorted six-coordinate octa-hedral geometry. It is coordinated by one chloride ligand, four N atoms from the (1R,2R)-N,N'-bis-[(quinolin-2-yl)methyl]cyclo-hexane-1,2-di-amine ligand, and a bridging oxido ligand attached to the second FeIII atom, which is also bonded to three chloride ions. A very weak intra-molecular N-H⋯Cl hydrogen bond occurs. In the crystal, the coordination complexes stack in columns, and a grouping of six such columns create channels, which are populated by disordered chloro-form solvent mol-ecules. Although the Fe-Cl bond lengths for the two metal atoms are comparable to the mean Fe-Cl bond lengths as derived from the Cambridge Structural Database, the Fe-O bond lengths are notably shorter. The solvent chloro-form mol-ecule exhibits 'flip' disorder of the C-H moiety in a 0.544 (3):0.456 (3) ratio. The only directional inter-action noted is a weak C-H⋯Cl hydrogen bond.

A new tecton with parallel halogen-bond donors: a path to supramolecular rectangles.

A new tecton, 1,8-diiodoethynylanthracene, with two halogen-bond donor sites was synthesized and characterized. This tecton is capable of forming two parallel halogen bonds at once, which makes it a useful building block for the construction of a variety of supramolecular squares and rectangles.

Probing Metal Ion Complexation of Ligands with Multiple Metal Binding Sites: The Case of Spiropyrans.

Among known molecular switches, spiropyrans attract considerable interest because of their reversible responsiveness to external stimuli and the deep conformational and electronic changes that characterize the switching process between the two isomeric forms [spiropyran (SP) and merocyanine (MC)]. Metal coordination is one of the most interesting aspects of spiropyrans for its potential in sensing, catalysis, and medicinal chemistry, but little is known about the details surrounding spiropyran-metal ion binding. We investigated the interplay between an N-modified 8-methoxy-6-nitrospiropyran (SP-E), designed to provide appropriate molecular flexibility and a range of competing/collaborative metal binding sites, with Mg2+ , Cu2+ and Zn2+ , which were chosen for their similar coordination geometry preferences while differing in their hard/soft character. The formed molecular complexes were studied by means of UV/Vis, fluorescence, and NMR spectroscopies and mass spectrometry, and the crystal structure of the SP-E-Cu complex was also obtained. The results indicate that the Mg2+ , Zn2+ and Cu2+ complexes have identical coordination stoichiometry. Furthermore, the Mg2+ and Zn2+ complexes display fluorescence properties in solution and visible-light responsiveness. These results provide important spectroscopic and structural information that can serve as a foundation for rational design of spiropyran-based smart materials for metal sensing and scavenging applications.

A systematic structural study of halogen bonding versus hydrogen bonding within competitive supramolecular systems.

As halogen bonds gain prevalence in supramolecular synthesis and materials chemistry, it has become necessary to examine more closely how such interactions compete with or complement hydrogen bonds whenever both are present within the same system. As hydrogen and halogen bonds have several fundamental features in common, it is often difficult to predict which will be the primary interaction in a supramolecular system, especially as they have comparable strength and geometric requirements. To address this challenge, a series of molecules containing both hydrogen- and halogen-bond donors were co-crystallized with various monotopic, ditopic symmetric and ditopic asymmetric acceptor molecules. The outcome of each reaction was examined using IR spectroscopy and, whenever possible, single-crystal X-ray diffraction. 24 crystal structures were obtained and subsequently analyzed, and the synthon preferences of the competing hydrogen- and halogen-bond donors were rationalized against a background of calculated molecular electrostatic potential values. It has been shown that readily accessible electrostatic potentials can offer useful practical guidelines for predicting the most likely primary synthons in these co-crystals as long as the potential differences are weighted appropriately.

Chemical synthesis of tetracyclic terpenes and evaluation of antagonistic activity on endothelin-A receptors and voltage-gated calcium channels.

A class of tetracyclic terpenes was synthesized and evaluated for antagonistic activity of endothelin-1 (ET-1) induced vasoconstriction and inhibitory activity of voltage-activated Ca(2+) channels. Three repeated Robinson annulation reactions were utilized to construct the tetracyclic molecules. A stereoselective reductive Robinson annulation was discovered for the formation of optically pure tricyclic terpenes. Stereoselective addition of cyanide to the hindered α-face of tetracyclic enone (-)-18 was found and subsequent transformation into the aldehyde function was affected by the formation of bicyclic hemiiminal (-)-4. Six selected synthetic tetracyclic terpenes show inhibitory activities in ET-1 induced vasoconstriction in the gerbil spiral modiolar artery with putative affinity constants ranging between 93 and 319 nM. Moreover, one compound, (-)-3, was evaluated further and found to inhibit voltage-activated Ca(2+) currents but not to affect Na(+) or K(+) currents in dorsal root ganglion cells under similar concentrations. These observations imply a dual mechanism of action. In conclusion, tetracyclic terpenes represent a new class of hit molecules for the discovery of new drugs for the treatment of pulmonary hypertension and vascular related diseases.

Crystal engineering of energetic materials: co-crystals of Ethylenedinitramine (EDNA) with modified performance and improved chemical stability.

In the area of energetic materials, co-crystallization is emerging as a new technology for modifying or enhancing the properties of existing energetic substances. Ethylenedinitramine (EDNA) is a known energetic material which requires attention partly due to its chemical instability originating with its two highly acidic protons. In order to stabilize EDNA, a co-crystallization approach targeting the acidic protons using a series of co-crystallizing agents with suitable hydrogen-bond acceptors was employed. Fifteen attempted co-crystallizations resulted in eight successful outcomes and six of these were crystallographically characterized and all showed evidence of hydrogen bonds to the intended protons. Calculated detonation properties and experimental thermal and impact data for the co-crystals were obtained and compared with those of pure EDNA. The co-crystal of EDNA and 1,2-bis(4-pyridyl)ethylene was recognized as a more thermally stable alternative to EDNA while the co-crystal of EDNA and pyrazine N,N'-dioxide showed comparable detonation strengths (and much improved chemical stability) compared with that of EDNA. The co-crystals EDNA:4,4'-bipyridine and EDNA:pyrazine N,N'-dioxide were found to be about 50 % less impact sensitive than EDNA, all of which illustrate how co-crystallizations can be utilized for successfully modifying specific aspects of energetic materials.

Stabilizing volatile liquid chemicals using co-crystallization.

A convenient, effective, and scalable protocol for stabilizing volatile liquid chemicals is reported. Through the use of halogen-bond driven co-crystal synthesis, several examples of liquid iodoperfluoroalkanes are transformed into crystalline materials with low-vapor pressure, considerable thermal stability, and moisture resistance. The target compounds can subsequently be re-generated through simple solvent-extractions.

Syntheses of 3-[(Alkylamino)methylene]-6-methylpyridine-2,4(1H,3H)-diones, 3-Substituted 7-Methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-dione Fluorescence Probes, and Tetrahydro-1H,9H-2,10-dioxa-9-azaanthracen-1-ones.

Various condensation and ring-closing reactions were used for the syntheses of 3-[(alkylamino)methylene]-6-methylpyri-dine-2,4(1H,3H)-diones, bicyclic pyridinones, and tricyclic morpholinopyrones. For instance, 3-[(dialkylamino)methylene]-6-methylpyridine-2,4(1H,3H)-diones were synthesized from the condensation of dialkylamines and 3-formyl-4-hydroxy-6-methylpyridin-2(1H)-one. 3-Formyl-4-hydroxy-6-methylpyridin-2(1H)-one, derived from 3-formyl-4-hydroxy-6-methylpyridin-2(1H)-one, was used to construct a number of bicyclic pyridinones via a one-pot Knoevenagal and intramolecular lactonization reaction. Tricyclic morpholinopyrones were assembled from a dialkylation reaction involving a dinucleophile, 3-amino-4-hydroxy-6-methyl-2H-pyran-2-one, and a dielectrophile, trans-3,6-dibromocyclohexene. Depending on the reaction conditions, isomers of the tricyclic molecules can be selectively produced, and their chemical structures were unequivocally determined using single-crystal X-ray analyses and 2D COSY spectroscopy. The fluorescently active bicyclic pyridinone compounds show longer absorption (368-430 nm; maximum) and emission wavelengths (450-467 nm) than those of 7-amino-4-methylcoumarin (AMC; λabs,max = 350 nm; λem = 430 nm) suggesting these molecules, such as 3-(2-aminoacetyl)-7-methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-dione, can be employed as fluorescence activity based probes for tracing biological pathways.

One-pot cascade approach to phenanthridine-fused quinazoliniminiums from heteroenyne-allenes.

A one-pot cascade method to obtain functionalized phenanthridine-fused quinazoliniminiums from a variety of heteroenyne-allenes is described. This protocol involves formation of C-N and C-C bonds in a single step in the presence of a Lewis acid and trace water to afford pentacyclic title compounds in moderate to good yields.

Supramolecular hierarchy among halogen-bond donors.

Through a combination of structural chemistry, vibrational spectroscopy, and theory, we have systematically examined the relative structure-directing importance of a series of ditopic halogen-bond (XB) donors. The molecular electrostatic potential surfaces of six XB donors were evaluated, which allowed for a charge-based ranking. Each molecule was then co-crystallized with 21 XB acceptors and the results have made it possible to map out the supramolecular landscape describing the competition between I/Br-ethynyl donors, perfluorinated I/Br donors, and I/Br-phenyl based donors. The results offer practical guidelines for synthetic crystal engineering driven by robust and directional halogen bonds.

Ranking relative hydrogen-bond strengths in hydroxybenzoic acids for crystal-engineering purposes.

Systematic co-crystallizations resulting in a total of six new crystal structures involving either 3-hydroxy- or 4-hydroxybenzoic acid, complemented by calculated molecular electrostatic potential surfaces and existing structural data, have shown that in a competitive molecular recognition situation, the -OH moiety is a more effective hydrogen-bond donor than the -COOH moiety which, in turn, highlights that electrostatic charge can offer more useful guidance than acidity for predicting competitive hydrogen-bond preferences.

Controlling molecular tautomerism through supramolecular selectivity.

We have isolated the stable as well as the metastable tautomers of 1-deazapurine in the solid state by exploiting principles of supramolecular selectivity in the context of cocrystal design.

A versatile and green mechanochemical route for aldehyde-oxime conversions.

A robust, facile and solvent-free mechanochemical path for aldehyde-oxime transformations using hydroxylamine and NaOH is explored; the method is suitable for aromatic and aliphatic aldehydes decorated with a range of substituents.

Diaqua-[(1R,2S,4R,8R,9S,11R)-2,9-di-methyl-1,4,8,11-tetra-aza-cyclo-tetra-decane]nickel(II) dichloride dihydrate.

The crystal structure of the title complex, [Ni(C(12)H(28)N(4))(H(2)O)(2)]Cl(2)·2H(2)O, displays O-H⋯Cl and O-H⋯O hydrogen bonding. The tetra-aza-cyclo-tetra-decane ligand inter-acts with the Ni(II) atom in the cis V configuration and the final two ligand binding sites are occupied by water.

Mono- and dinuclear nickel(II) complexes of resolved Schiff-base ligands with extended quinoline substituents.

The coordination chemistry of four enantiopure tetradentate bis(iminoquinoline) ligands with nickel(II) salts is reported. The previously reported ligands CBQ, CPQ, BBQ, and BPQ result from the condensation of (1R,2R)-cyclohexyldiamine or (R)-BINAM with two equivalents of 2-formylbenzo[h]quinoline or 8-isopropyl-2-quinolinecarboxaldehyde {CBQ = (1R,2R)-cyclohexanediamine-N,N'-bis(benzo[h]quinoline-2-ylmethylene), CPQ = (1R,2R)-cyclohexanediamine-N,N'-bis[[(8-isopropyl)-2-quinolinyl]methylene], BBQ = [(R)-1,1'-binaphthalene]-2,2'-diamine-N,N'-bis(benzo[h]quinoline-2-ylmethylene), BPQ = [(R)-1,1'-binaphthalene]-2,2'-diamine-N,N'-bis[[(8-isopropyl)-2-quinolinyl]methylene]}. Reaction of NiI(2) with the (1R,2R)-cyclohexyl ligands gives the mononuclear distorted trigonal-bipyramidal (TBP) complexes [Ni(N(3)-CBQ)I(2)] and [Ni(N(3)-CPQ)I(2)]. Incomplete iodide abstraction from [Ni(N(3)-CPQ)I(2)] with AgOTf leads to partial replacement of the iodide with hydroxide from adventitious water to give [Ni(N(3)-CPQ)I(1.6)(OH)(0.4)] (distorted TBP). The corresponding reaction with [Ni(N(3)-CBQ)I(2)] again fails to remove all of the iodide, resulting instead in conversion to the syn dinuclear [Ni(2)(CBQ)(µ-X)(2)I(2)] (X = Cl(0.925)I(0.075)) complex, where chloride abstraction from the solvent (CH(2)Cl(2)) has resulted in a mixed halide system and the metal centers are square-pyramidal. Reaction of Ni(OTf)(2) with CBQ leads to the isolation of the octahedral cation [Ni(CMBQ)(2)](2+), with CMBQ [(1R,2R)-cyclohexanediamine-mono-N-(benzo[h]quinoline-2-ylmethylene)] being the partial hydrolysis product of CBQ. [Ni(CMBQ)(2)][OTf](2) crystallizes as a 1:1 mixture of P and M helical diastereomers. The coordination of NiI(2) with the (R)-BINAM derived ligands yields the anti dinuclear P-helical complexes [Ni(2)(BBQ)(µ-I)(2)I(2)] and [Ni(2)(BPQ)(µ-I)(2)I(2)]: one nickel ion is coordinated in each bidentate iminoquinoline pocket and the geometry at the metal centers is distorted square-pyramidal. Characterisation by (1)H NMR, UV-Vis, electronic circular dichroism (ECD) spectroscopy, combustion analysis, and HRMS is reported in addition to structural and halide abstraction studies.

Synthesis and antiviral activity of substituted quercetins.

Influenza viruses are important pathogens that cause respiratory infections in humans and animals. In addition to vaccination, antiviral drugs against influenza virus play a significant role in controlling viral infections by reducing disease progression and virus transmission. Plant derived polyphenols are associated with antioxidant activity, anti-carcinogenic, and cardio- and neuro-protective actions. Some polyphenols, such as resveratrol and epigallocatechin gallate (EGCG), showed significant anti-influenza activity in vitro and/or in vivo. Recently we showed that quercetin and isoquercetin (quercetin-3-ß-d-glucoside), a glucoside form of quercetin, significantly reduced the replication of influenza viruses in vitro and in vivo (isoquercetin). The antiviral effects of isoquercetin were greater than that of quercetin with lower IC(50) values and higher in vitro therapeutic index. Thus, we investigated the synthesis and antiviral activities of various quercetin derivatives with substitution of C3, C3', and C5 hydroxyl functions with various phenolic ester, alkoxy, and aminoalkoxy moieties. Among newly synthesized compounds, quercetin-3-gallate which is structurally related to EGCG showed comparable antiviral activity against influenza virus (porcine H1N1 strain) to that of EGCG with improved in vitro therapeutic index.

Hydrogen-bond driven assembly of a molecular capsule facilitated by supramolecular chelation.

Resorcinarene-based cavitands functionalized with acetamido groups capable of self-complementary hydrogen-bond interactions, were synthesized in order to construct supramolecular capsules. The 1,3-bifunctionalized cavitand produced a polymeric assembly, whereas the tetra-functionalized analogue yielded a discrete capsule held together via N-H···O hydrogen bonds. The ethynyl species attached to the rim of these host molecules deepen each cavitand and expands the volume of the resulting capsule.