Showing papers by "Alexander J. Blake published in 2007"

Multilayer PDMS microfluidic chamber for controlling brain slice microenvironment

Abstract: A novel three-layer microfluidic polydimethylsiloxane (PDMS) device was constructed with two fluid chambers that holds a brain slice in place with microposts while maintaining laminar perfusate flow above and below the slice. Our fabrication technique permits rapid production of PDMS layers that can be applied to brain slices of different shapes and sizes. In this study, the device was designed to fit the shape and thickness (530–700 µm) of a medullary brain slice taken from P0–P4 neonatal rats. Medullary slices in this chamber spontaneously produced rhythmic, respiratory-related motor output for up to 3 h, thereby demonstrating that brain slice viability was maintained for prolonged periods. This design is unique in that it achieves independent control of fluids through multiple channels in two separate fluid chambers. The laminar flow exhibited by the microfluidic chamber allows controlled solutions to target specific areas of the brain slice based on the input flow rates. To demonstrate this capability, a stream of Na+-free solution was focused on one half of a medullary slice to abolish spontaneous neural activity in only that half of the brain slice, while the other half remained active. We also demonstrated that flow of different solutions can be focused over the midline of the brain slice. The multilayer brain slice chamber design can integrate several traditional types of electrophysiology tools that are commonly used to measure neurophysiological properties of brain slices. Thus, this new microfluidic chamber is advantageous for experiments that involve controlled drug or solution delivery at high spatiotemporal resolution.

Synthesis of polyprenylated acylphloroglucinols using bridgehead lithiation: the total synthesis of racemic clusianone and a formal synthesis of racemic garsubellin A.

Abstract: The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the late intermediates in the Danishefsky synthesis.

Design and synthesis of binucleating macrocyclic clefts derived from Schiff-base calixpyrroles.

Abstract: The syntheses, characterisation and complexation reactions of a series of binucleating Schiff-base calixpyrrole macrocycles are described. The acid-templated [2+2] condensations between meso-disubstituted diformyldipyrromethanes and o-phenylenediamines generate the Schiff-base pyrrolic macrocycles H4L1 to H4L6 upon basic workup. The single-crystal X-ray structures of both H4L3⋅2 EtOH and H4L6⋅H2O confirm that [2+2] cyclisation has occurred, with either EtOH or H2O hydrogen-bonded within the macrocyclic cleft. A series of complexation reactions generate the dipalladium [Pd2(L)] (L=L1 to L5), dinickel [Ni2(L1)] and dicopper [Cu2(L)] (L=L1 to L3) complexes. All of these complexes have been structurally characterised in the solid state and are found to adopt wedged structures that are enforced by the rigidity of the aryl backbone to give a cleft reminiscent of the structures of Pacman porphyrins. The binuclear nickel complexes [Ni2(μ-OMe)2Cl2(HOMe)2(H4L1)] and [Ni2(μ-OH)2Cl2(HOMe)(H4L5)] have also been prepared, although in these cases the solid-state structures show that the macrocyclic ligand remains protonated at the pyrrolic nitrogen atoms, and the NiII cations are therefore co-ordinated by the imine nitrogen atoms only to give an open conformation for the complex. The dicopper complex [Cu2(L3)] was crystallised in the presence of pyridine to form the adduct [Cu2(py)(L3)], in which, in the solid state, the pyridine ligand is bound within the binuclear molecular cleft. Reaction between H4L1 and [Mn(thf){N(SiMe3)2}2] results in clean formation of the dimanganese complex [Mn2(L1)], which, upon crystallisation, formed the mixed-valent complex [Mn2(μ-OH)(L1)] in which the hydroxo ligand bridges the metal centres within the molecular cleft.

Versatility of 2,6-diacetylpyridine (dap) hydrazones in generating varied molecular architectures: synthesis and structural characterization of a binuclear double helical Zn(II) complex and a Mn(II) coordination polymer.

Abstract: A binuclear complex of Zn(II) with formula [Zn(dap(A)2)]2·2.25DMF (2·2.25DMF) and a Mn(II) coordination polymer with formula [Mn3(dap(In)2)3(H2O)2·2DMSO]n (3·2DMSO)n have been prepared and structurally characterized [dap(A)2 = dideprotonated form of 2,6-diacetylpyridine bis(anthraniloyl hydrazone); dap(In)2 = doubly deprotonated form of 2,6-diacetylpyridine bis(isonicotinoyl hydrazone)]. In the Zn(II) complex the molecular units are double helical, with the Zn(II) ions in a square pyramidal environment. The Mn(II) complex on the other hand is a coordination polymer containing two different types of hepta-coordinated Mn(II) ions, which differ in their axial ligands. The magnetic properties of the Mn(II) complex, along with those of a double helical pyridine bridged binuclear Ni(II) complex, earlier synthesized by us, are also reported. The ability of the 2,6-diacetylpyridine bis(aroyl hydrazone) ligands to form double helical complexes is analyzed in terms of the conformational flexibility of the ligands. The differences in the magnetic properties of the µ-N bridged binuclear complexes formed by 1,1 azido N-bridging ligands, and pyridine N-bridging ligands, is analyzed with the help of EHMO calculations.

Tuning the selectivity/specificity of fluorescent metal ion sensors based on N2S2 pyridine-containing macrocyclic ligands by changing the fluorogenic subunit: spectrofluorimetric and metal ion binding studies.

Abstract: Two new fluorescent chemosensors for metal ions have been synthesized and characterized, and their photophysical properties have been explored; they are the macrocycles 5-(2-quinolinylmethyl)-2,8-dithia-5-aza-2,6-pyridinophane (L5) and 5-(5-chloro-8-hydroxyquinolinylmethyl)-2,8-dithia-5-aza-2,6-pyridinophane (L6). Both systems have a pyridyl-thioether-containing 12-membered macrocycle as a binding site. The coordination properties of these two ligands toward CuII, ZnII, CdII, HgII, and PbII have been studied in MeCN/H2O (1:1 v/v) and MeCN solutions and in the solid state. The stoichiometry of the species formed at 25 C have been determined from absorption, fluorescence, and potentiometric titrations. The complexes [CuL5](ClO4)2·1/2MeCN, [ZnL5(H2O)](ClO4)2, [HgL5(MeCN)](ClO4)2, [PbL5(ClO4)2], [Cu3(5-Cl-8-HDQH-1)(L6H-1)2](ClO4)3·7.5H2O (HDQ = hydroxyquinoline), and [Cu(L6)2](BF4)2·2MeNO2 have also been characterized by X-ray crystallography. A specific CHEF-type response of L5 and L6 to the presence of ZnII and CdII, respectively, has been observed at about pH 7.0 in MeCN/H2O (1:1 v/v) solutions.

Anion selectivity in zwitterionic amide-functionalised metal salt extractants

Abstract: Amide-functionalised salen ligands capable of extracting metal salts have been synthesised and characterised. Single-crystal X-ray structure determinations of complexes of NiSO4, [Ni(L)(SO4)], confirm that the ionophores are in a zwitterionic form with Ni(II) bound in the deprotonated salen moiety and the SO4(2-) ion associated with protonated pendant N'-amidopiperazine groups. Treatment of [Ni(L)(SO4)] with base removes the protons from the pendant amido-amine group resulting in loss of the SO4(2-) ion and formation of metal-only complexes of type [Ni(L-2H)], which have been characterized by single-crystal X-ray diffraction. Three of the ligands with solubilities suitable for solvent extraction studies show loading and stripping pH-profiles that are suitable for the recovery of CuSO4 or CuCl2 from industrial leach solutions. The copper-only complexes, [Cu(L-2H)], are selective for Cl- over SO4(2-) in both solvent extraction and bulk liquid membrane transport experiments and were found to bind Cl- in two steps via the formation of a 1:1:1 [Cu(L-H)Cl] assembly, followed by a 1:1:2 [Cu(L)Cl2] assembly as the pH of the aqueous phase is lowered. The anion transport selectivity was evaluated for a number of other mono-charged anions and interestingly the ligands were found to display a preference for the Br- ion. To probe the influence of the Hofmeister bias on the selectivity of anion complexation, single-phase potentiometric titration experiments were employed to investigate the binding of SO4(2-) and Cl- by one of the copper only complexes, [Cu(L-2H)] in 95 %/5 % MeOH/water. Under these conditions selectivity was reversed (SO4(2-)>Cl-) confirming that the Hofmeister bias, which reflects the relative hydration energies of the anions, dominates the selectivity of anion extraction from aqueous media into CHCl3.

Demonstration of Promoted Zinc Schlenk Equilibria, their Equilibrium Values and Derived Reactivity

Abstract: The presence of promoted Schlenk equilibria for organozinc halide species has been explicitly demonstrated by 13C NMR studies. Thus, addition of methylaluminoxane (MeAlO)n, MAO, to RZnX (R=Et, Bn, ArCH2, (CH2)3CO2Et; X=Cl, Br) leads to the formation of ZnR2 and ZnX2⋅MAO. For EtZnCl, equilibration of ZnEt2 and ZnX2⋅MAO is rapid at −35 °C; a K value of 0.19 M−1 indicates the equilibrium favours ZnEt2 (0.75–3.0 equiv MAO). Use of RZnX/MAO mixtures allows copper-catalysed 1,4-addition to 2-cyclohexenone to be achieved, but a competing cascade reaction (two subsequent Michael additions and an intramolecular aldol reaction) leads to novel tetracyclic by-products (characterised crystallographically in one case). Activation of EtZnCl is also achieved by ZnMe2 addition and the presence of intermediate EtZnMe was observed by 13C NMR spectroscopy (at equilibrium, K≈1). Asymmetric conjugate addition in this system can be realised (up to 92 % ee for additions to 2-cyclohexenone).

New fluorescent chemosensors for heavy metal ions based on functionalized pendant arm derivatives of 7-anthracenylmethyl-1,4,10-trioxa-7,13-diazacyclopentadecane.

Abstract: 7-anthracenylmethyl-13-methylpyridyl-1,4,10-trioxa-7,13-diazacyclopentadecane (L4) and 7-anthracenylmethyl-13-(2,2-dimethyl-2-hydroxyethyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (L5) have been synthesized and characterized. Both derive from 7-anthracenylmethyl-1,4,10-trioxa-7,13-diazacyclopentadecane (L3) and differ for having a differently functionalized pendant arm covalently attached to the remaining secondary nitrogen donor of the macrocyclic framework. The protonation and coordination behavior of L4, L5, and the unbranched L3 with metal ions have been studied in MeCN/H2O (1:1 v/v, 298.1 K, I = 0.1 M) using potentiometric methods. The crystal structures of L3, [(H2L3)(HL3)](ClO4)3, and the complex [CdL3(NO3)2] have been determined by single-crystal X-ray methods. The fluorescent behavior of L3-L5 in the presence of CuII, ZnII, CdII, HgII, and PbII has been studied as a function of pH in MeCN/H2O (1:1 v/v). The presence of CuII, HgII, or PbII does not affect the fluorescent behavior observed for the three free ligands upon changing the pH. Interestingly, the fluorescent emission of L3 and L5 is selectively enhanced only in the presence of CdII at basic pH. The same effect is observed for L4 in the presence of CdII or ZnII at about pH 7.

Synthesis, characterization, and crystal structure of [Ni(dap(A) 2 )] 2 (dap(AH) 2 : 2,6-diacetylpyridine bis(anthraniloyl hydrazone))—a molecule possessing an infinite double helical chain in the solid state

Abstract: Anthraniloyl hydrazide (AH) contains two −NH2 groups, one of them is attached to the aromatic ring and the other is the hydrazinic, −NH2. It is found that only the later reacts with the carbonyl compounds to form Schiff bases, while the former remains inert. The reasons behind this difference in reactivity are analyzed on the basis of semi-empirical calculations, which show that the lone pair of the ring −NH2 is considerably delocalized over the ring, resulting in an accumulation of a positive charge on this particular nitrogen. Ni(II) complex of 2,6-diacetylpyridine bis(anthraniloyl hydrazone) has been prepared and characterized by various physico-chemical methods. The structure of the complex was determined by X-ray crystallography. It was found that in the solid state, the compound exist as a dimer, and two coordinated ligand moieties form a double helix around the two metal ions. H-bonding then results in extension of double helix to an infinite chain.

Extended structures of polyiodide salts of transition metal macrocyclic complexes

Abstract: The structures of five polyiodide salts, [Co([9]aneS3)2]I11 (1), [Ni([9]aneS3)2]I6 (2), [Ni([9]aneS3)2]I10 (3), [Pd([12]aneS4)]I6 (4) and [Pd([14]aneS4)]I10·MeCN (5), containing the template cations [Co([9]aneS3)2]3+, [Ni([9]aneS3)2]2+, [Pd([12]aneS4)]2+ and [Pd([14]aneS4)]2+ ([9]aneS3 = 1,4,7-trithiacyclononane, [12]aneS4 = 1,4,7,10-tetrathiacyclododecane, [14]aneS4 = 1,4,8,11-tetrathiacyclotetradecane) exhibit a range of polyiodide and polyanionic framework structures. In (1) the charge on the CoIII cation is balanced by three I_3^- anions, which along with a neutral di-iodine molecule form I_{11}^{3-} rings in an extended structure comprising undulating chains of alternating I_{11}^{3-} rings and complex cations. In (2) the complex cation is linked to two tri-iodide anions by S⋯I interactions into well separated sheets of cations and anions, while in (3), I_5^- anions are linked by I⋯I interactions into helices which are cross-linked by S⋯I contacts to form sheets. Rather longer I⋯I contacts in (4) assemble I_3^- ions into 2 × 2 rods, which are linked into a three-dimensional network by S⋯I contacts. In (5) the N atom of the acetonitrile solvent molecule forms an array of four weak C—H⋯N hydrogen bonds to the macrocycle. The extended structure comprises corrugated zigzag chains of polyiodide rings formed by linked I_5^- units; the complex cations are attached to the polyiodide network by S⋯I contacts, which link the chains to form layers.

(1,3-Dimethylimidazolidine-2-selone-κSe)bis(1,10-phenanthroline-κ2N,N′)copper(II) bis(perchlorate) and bis(2,2′-bipyridyl-κ2N,N′)(imidazolidine-2-thione-κS)copper(II) bis(perchlorate)

Abstract: In the first title salt, [Cu(C12H8N2)2(C5H10N2Se)](ClO4)2, the CuII centre occupies a distorted trigonal–bipyramidal environment defined by four N donors from two 1,10-phenanthroline (phen) ligands and by the Se donor of a 1,3-dimethyl­imidazolidine-2-selone ligand, with the equatorial plane defined by the Se and by two N donors from different phen ligands and the axial sites occupied by the two remaining N donors, one from each phen ligand. The Cu—N distances span the range 1.980 (10)–2.114 (11) A and the Cu—Se distance is 2.491 (3) A. Inter­molecular π–π contacts between imidazolidine rings and the central rings of phen ligands generate chains of cations. In the second salt, [Cu(C10H8N2)2(C3H6N2S)](ClO4)2, the CuII centre occupies a similar dis­torted trigonal–bipyramidal environment comprising four N donors from two 2,2′-bipyridyl (bipy) ligands and an S donor from an imidazolidine-2-thione ligand. The equatorial plane is defined by the S donor and two N donors from different bipy ligands. The Cu—N distances span the range 1.984 (6)–2.069 (7) A and the Cu—S distance is 2.366 (3) A. Inter­molecular π–π contacts between imidazolidine and pyridyl rings form chains of cations. A major difference between the two structures is due to the presence in the second complex of two N—H⋯O hydrogen bonds linking the imidazolidine N—H hydrogen-bond donors to perchlorate O-atom acceptors.

In Search of New Approaches to Asymmetric Conjugate Addition: Screening Studies on the Use of [Zn(bpy*)X(R)] Reagents and α,β-Unsaturated Amide Michael Acceptors

Abstract: Conjugate additions of [Zn(bpy*)Cl(Et)] (bpy* = 4,4'-di- tert -butyl-2,2'-bipyridine) to cyclohex-2-en-1-one are promoted by ZnMe 2 in 88% ee but in moderate yield under Cu I phosphoramidite catalysis. In the absence of ZnMe 2 the [Zn(bpy*)Cl(Et)] is inactive indicating a Schlenk-type equilibrium. Other derivatives of [Zn(bpy*)Cl(R)] (R = Bu, 4-methylbenzyl), prepared in situ from [ZnCl(R)] and the bipyridine give low yields due to competing chloride abstraction. 13 C NMR studies indicate facile organo-ligand exchange between [Zn(bpy*)(Et) 2 ] and [Zn(bpy*)Cl 2 ] complexes. In the presence of the bipyridine, [ZnBr(allyl)] disproportionates into [Zn(bpy*)Br 2 ] and [Zn(bpy*)(allyl) 2 ] species. In separate studies, simple ( E )-MeCH=CHCONMeR (R = Me, OMe) α,β-unsaturated amides undergo asymmetric 1,4-addition of EtMgBr in 75-99% yield and 48-79% ee in the presence of the diphosphines JosiPhos or MeDuPhos and copper(I) sources.

Inclusion of molecular iodine into channels of the organic zeolite-like gossypol

Abstract: Gossypol has been obtained in the zeolite-like form by desolvation of the 1:1 unstable solvate with dichloromethane. It demonstrates a high potential for an uptake of molecular iodine from the environment. In a case of single crystals a stable inclusion compound (gossypol)8·I2, preserving the crystal structure of the zeolite-like form, has been prepared. The iodine molecules occupy large cavities of the channels and are inclined as confirmed by the absence of a strong dichroism. The iodine molecules can be removed with the help of vacuum giving back to the zeolite-like form.

Synthesis of Polyprenylated Acylphloroglucinols Using Bridgehead Lithiation: The Total Synthesis of Racemic Clusianone and a Formal Synthesis of Racemic Garsubellin A.

Abstract: The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the late intermediates in the Danishefsky synthesis.

Dimethyl 2,2′‐bipyridine‐6,6′‐dicarboxylate and bis(dimethyl 2,2′‐bipyridine‐6,6′‐dicarboxylato‐κ2N,N′)copper(I) tetrafluoroborate

Abstract: The single-crystal X-ray structures of dimethyl 2,2'-bipyridine-6,6'-dicarboxylate, C(14)H(12)N(2)O(4), and the copper(I) coordination complex bis(dimethyl 2,2'-bipyridine-6,6'-dicarboxylato-kappa(2)N,N')copper(I) tetrafluoroborate, [Cu(C(14)H(12)N(2)O(4))(2)]BF(4), are reported. The uncoordinated ligand crystallizes across an inversion centre and adopts the anticipated anti pyridyl arrangement with coplanar pyridyl rings. In contrast, upon coordination of copper(I), the ligand adopts an arrangement of pyridyl donors facilitating chelating metal coordination and an increased inter-pyridyl twisting within each ligand. The distortion of each ligand contrasts with comparable copper(I) complexes of unfunctionalized 2,2'-bipyridine.

Synthesis Towards Complex Bridged Alkaloids Derived from Diketopiperazines: A Cationic Cascade Approach to Stephacidins, Paraherquamides and Related Systems.

Abstract: Regioselective enolate formation, followed by stereoselective electrophilic quenching of unsymmetrical proline-derived diketopiperazines (DKPs), enabled the synthesis of variously substituted DKPs, including one substrate which could be further substituted and cyclised to give the bicyclo[2.2.2]diazaoctane core structure present in paraherquamide and stephacidin natural products.