Efficient Stille cross-coupling reaction using aryl chlorides or bromides in water

An efficient Stille cross-coupling reaction using a variety of aryl halides in neat water has been developed. Employing palladium-phosphinous acid catalyst [(t-Bu)(2)P(OH)](2)PdCl(2) allows formation of biaryls from aryl chlorides and bromides in good to high yields. Functional groups such as ketones and nitriles are tolerated, and organic cosolvents are not required. The air stability and solubility in water of the palladium complexes used in this study facilitate operation of the coupling reaction and product isolation. The feasibility of catalyst recycling has also been demonstrated.     

Enzyme control of small-molecule coordination in FosA as revealed by 31P pulsed ENDOR and ESE-EPR

FosA is a manganese metalloglutathione transferase that confers resistance to the broad-spectrum antibiotic fosfomycin, which contains a phosphonate group. The active site of this enzyme consists of a high-spin Mn(2+) ion coordinated by endogenous ligands (a glutamate and two histidine residues) and by exogenous ligands, such as substrate fosfomycin. To study the Mn(2+) coordination environment of FosA in the presence of substrate and the inhibitors phosphonoformate and phosphate, we have used (31)P pulsed electron-nuclear double resonance (ENDOR) at 35 GHz to obtain metrical information from (31)P-Mn(2+) interactions. We have found that continuous wave (CW) (31)P ENDOR is not successful in the study of phosphates and phosphonates coordinated to Mn(2+). Parallel studies of phosph(on)ate binding to the Mn(2+) of FosA and to aqueous Mn(2+) ion disclose how the enzyme modifies the coordination of these molecules to the active site Mn(2+). Through analysis of (31)P hyperfine parameters derived from simulations of the ENDOR spectra we have determined the binding modes of the phosph(on)ates in each sample and discerned details of the geometric and electronic structure of the metal center. The (31)P ENDOR studies of the protein samples agree with, or improve on, the Mn-P distances determined from crystal structures and provide Mn-phosph(on)ate bonding information not available from these studies. Electron spin echo electron paramagnetic resonance (ESE-EPR) spectra have also been recorded. Simulation of these spectra yield the axial and rhombic components of the Mn(2+) (S = (5)/(2)) zero-field splitting (zfs) tensor. Comparison of structural inferences based on these zfs parameters both with the known enzyme structures and the (31)P ENDOR results establishes that the time-honored procedure of analyzing Mn(2+) zfs parameters to describe the coordination environment of the metal ion is not valid or productive.     

Conformational and spacial preferences for substrates of PepT1

The conformation at the first residue of dipeptide substrates for the peptide transporter PepT1 has been probed using constrained peptide analogues, and the active conformation has been identified.     

On the Diels-Alder reactions of pentadienyl maleates and citraconates

Reactions between conjugated dienols and maleic anhydride provide either cis-fused or trans-fused bicyclic products as major products, depending upon how the reaction is carried out. Simply mixing the two reactants together generally leads to cis-fused lactone acids in thermal reactions which proceed viaintermolecular Diels-Alder reaction followed by intramolecular esterification. Pre-forming the maleate half ester derivative followed by heating affords predominantly trans-fused lactone acids in good yields by way of an intramolecular Diels-Alder (IMDA) reaction. Sorbyl citraconate half esters undergo a rapid thermolytic fragmentation in refluxing toluene to form the dienol and citraconic anhydride. The resulting diene-dienophile pair undergo an intermolecular cycloaddition followed by a rapid intramolecular esterification to give cis-fused bicyclic lactone acids as major products. The IMDA reaction of citraconic half esters is sufficiently rapid in DMSO to dominate over fragmentation: the exo-cycloadduct is formed almost exclusively. Nine literature reports of endo-selective IMDA reactions of triene acids are erroneous; the cycloadditions proceed in an intermolecular manner.     

In-Situ Investigation of Discolouration Processes Between Historic Oil Paint Pigments

Discolouring interactions between paint pigments have been observed since the mid 19^th century. The source of some of these discolourations is the production of copper sulfides from an interaction between cadmium sulfide pigments and copper containing pigments. In this work, the discolouring interaction between cadmium yellow and malachite pigments was observed dynamically using the environmental scanning electron microscope (ESEM).     

Synthesis of 1,3-disubstituted bicyclo[1.1.0]butanes via directed bridgehead functionalization

Bicyclo[1.1.0]butanes (BCBs) are increasingly valued as intermediates in ‘strain release’ chemistry for the synthesis of substituted four membered rings and bicyclo[1.1.1]pentanes, with applications including bioconjugation processes. Variation of the BCB bridgehead substituents can be challenging due to the inherent strain of the bicyclic scaffold, often necessitating linear syntheses of specific BCB targets. Here we report the first palladium catalyzed cross-coupling on pre-formed BCBs which enables a ‘late stage’ diversification of the bridgehead position, and the conversion of the resultant products into a range of useful small ring building blocks.

Bicyclo[1.1.0]butanes (BCBs) are valuable precursors to four-membered rings and bicyclo[1.1.1]pentanes, and useful bioconjugation agents. We describe a versatile approach to access 1,3-disubstituted BCBs, which are otherwise challenging to prepare.     

Interlayer adsorption of polyvinylpyrrolidone on montmorillonite

Two methods (x-ray diffraction and desorption of ¹⁰⁹Cd and ⁸⁵Sr) were used to provide indirect evidence for the adsorption of polyvinylpyrrolidone (PVP) on the surface of montmorillonite. It was shown that by decreasing the number of solvent layers in the interlayer distance the amount of adsorbed PVP was decreased, indicating that attachment of the polymer to the tetrahedral sheets is likely to occur. Desorption of radio-nuclides from calcium and sodium montmorillonites confirmed this hypothesis.     

Single-molecule magnets: preparation and properties of low symmetry [Mn4O3(O2CPh-R)4(dbm)3] complexes with S = 9/2

The preparation and properties of [Mn(4)O(3)(O(2)CPh-R)(4)(dbm)(3)] (R = H, p-Me, p-OMe, and o-Cl; dbm(-) is the anion of dibenzoylmethane) single-molecule magnets (SMMs) with virtual C(S) symmetry are reported. They were prepared by controlled potential electrolysis in 26-80% yields. The structures comprise a distorted-cubane core of virtual C(S) symmetry, in contrast to the other, more common complexes of this type with virtual C(3)(V) symmetry. Solid-state magnetic susceptibility data establish the complexes have S = 9/2 ground-state spins, and ac susceptibility studies indicate they are single-molecule magnets (SMMs). Magnetization vs dc field sweeps below 1.00 K reveal hysteresis loops confirming a SMM, with a very large step at zero applied field diagnostic of fast quantum tunneling of magnetization (QTM) through the anisotropy barrier. The fast QTM rate suggested a significant rhombic ZFS parameter E, as expected from the low (virtual C(S)) symmetry. This was confirmed by high-frequency electron paramagnetic resonance spectroscopy on polycrystalline and single-crystal studies. The results confirm the importance of symmetry on the QTM rates.     

ThX – a next-generation probe for the early detection of amyloid aggregates

Neurodegenerative diseases such as Alzheimer''s and Parkinson''s are associated with protein misfolding and aggregation. Recent studies suggest that the small, rare and heterogeneous oligomeric species, formed early on in the aggregation process, may be a source of cytotoxicity. Thioflavin T (ThT) is currently the gold-standard fluorescent probe for the study of amyloid proteins and aggregation processes. However, the poor photophysical and binding properties of ThT impairs the study of oligomers. To overcome this challenge, we have designed Thioflavin X, (ThX), a next-generation fluorescent probe which displays superior properties; including a 5-fold increase in brightness and 7-fold increase in binding affinity to amyloidogenic proteins. As an extrinsic dye, this can be used to study unique structural amyloid features both in bulk and on a single-aggregate level. Furthermore, ThX can be used as a super-resolution imaging probe in single-molecule localisation microscopy. Finally, the improved optical properties (extinction coefficient, quantum yield and brightness) of ThX can be used to monitor structural differences in oligomeric species, not observed via traditional ThT imaging.

Introducing ThX, a next-generation ThT derivative that allows for the early detection of amyloid aggregates at the bulk and single-aggregate levels.     

Columnar mesomorphism from hemi-disklike metallomesogens derived from 2,6-bis[3',4',5'-tri(alkoxy)phenyliminomethyl]pyridines (L): crystal and molecular structures of [M(L)Cl2] (M=Mn,Ni, Zn)

Four new series of non-disklike complexes of general formula [MCl(2)(L(n))] based upon substituted 2,6-bis(3',4',5'-trialkoxyphenyliminomethyl)pyridine ligands (L(n)) and with M=Zn(II), Co(II), Mn(II), and Ni(II) have been prepared and examined for liquid crystallinity. A complete analysis of the thermal behavior by polarized-light optical microscopy, differential scanning calorimetry, and small-angle Xray scattering revealed a rich and varied mesomorphism. Moreover, the high thermal stability of the compounds leads to rather extended mesomorphic ranges. The nature and thermal stability of each mesophase depend on both the length of the six terminal alkoxy chains, n (n=8, 10, 12, 14, 16), and on the metal ions. As demonstrated by small-angle Xray diffraction experiments, the mesomorphism of these complexes is solely of the columnar type. One compound shows an oblique columnar phase, while most of them show a hexagonal columnar phase, Col(h), and several types of rectangular columnar phase, Col(r). Xray single-crystal structures obtained for three methoxy derivatives confirm the 1:1 metal-ligand stoichiometry of the complexes, in which the metal is pentacoordinate with a distorted, trigonal bipyramidal geometry. The crystalline structures also reveal the existence of some columnar organization in the solid state, the columns resulting from an alternated stacking of the complexes in one direction. By combining these results with those obtained from dilatometry experiments, a model for the molecular organization within the mesophases is proposed in which an antiparallel arrangement of the metallomesogens is retained in the mesophase.