Syntheses, structures, and reactivity of new pentamethylcyclopentadienyl-rhodium(III) and -iridium(III) 4-acyl-5-pyrazolonate complexes

New [CpM(Q)Cl] complexes (M = Rh or Ir, Cp = pentamethylcyclopentadienyl, HQ = 1-phenyl-3-methyl-4R(C=O)-pyrazol-5-one in general, in detail HQ(Me), R = CH(3); HQ(Et), R = CH(2)CH(3); HQ(Piv), R = CH(2)-C(CH(3))(3); HQ(Bn), R = CH(2)-(C(6)H(5)); HQ(S), R = CH-(C(6)H(5))(2)) have been synthesized from the reaction of [CpMCl(2)](2) with the sodium salt, NaQ, of the appropriate HQ proligand. Crystal structure determinations for a representative selection of these [CpM(Q)Cl] compounds show a pseudo-octahedral metal environment with the Q ligand bonded in the O,O'-chelating form. In each case, two enantiomers (S(M)) and (R(M)) arise, differing only in the metal chirality. The reaction of [CpRh(Q(Bn))Cl] with MgCH(3)Br produces only halide exchange with the formation of [CpRh(Q(Bn))Br]. The [CpRh(Q)Cl] complexes react with PPh(3) in dichloromethane yielding the adducts CpRh(Q)Cl/PPh(3) (1:1) which exist in solution in two different isomeric forms. The interaction of [CpRh(Q(Me))Cl] with AgNO(3) in MeCN allows generation of [CpRh(Q(Me))(MeCN)]NO(3).3H(2)O, whereas the reaction of [CpRh(Q(Me))Cl] with AgClO(4) in the same solvent yields both [CpRh(Q(Me))(H(2)O)]ClO(4) and [CpRh(Cl)(H(2)O)(2)]ClO(4); the H(2)O molecules derive from the not-rigorously anhydrous solvents or silver salts.     

Formation and characterization of the hexanuclear platinum cluster [Pt6(mu-PBu(t)2)4(CO)6](CF3SO3)2 through structural, electrochemical, and computational analyses

The reaction between equimolar amounts of Pt(3)(mu-PBu(t)()(2))(3)(H)(CO)(2), Pt(3)()H, and CF(3)SO(3)H under CO atmosphere affords the triangular species [Pt(3)(mu-PBu(t)()(2))(3)(CO)(3)]X, [Pt(3)()(CO)(3)()(+)()]X (X = CF(3)SO(3)(-)), characterized by X-ray crystallography, or in an excess of acid, [Pt(6)(mu-PBu(t)()(2))(4)(CO)(6)]X(2), [Pt(6)()(2+)()]X(2)(). Structural determination shows the latter to be a rare hexanuclear cluster with a Pt(4) tetrahedral core formed by joining the unbridged sides of two orthogonal Pt(3) triangles. The dication Pt(6)()(2+)() features also extensive redox properties as it undergoes two reversible one-electron reductions to the congeners [Pt(6)(mu-PBu(t)()(2))(4)(CO)(6)](+) (Pt(6)()(+)(), E(1/2) = -0.27 V) and Pt(6)(mu-PBu(t)()(2))(4)(CO)(6) (Pt(6)(), E(1/2) = -0.54 V) and a further quasi-reversible two-electron reduction to the unstable dianion Pt(6)()(2)()(-)() (E(1/2) = -1.72 V). The stable radical (Pt(6)()(+)()) and diamagnetic (Pt(6)()) species are also formed via chemical methods by using 1 or 2 equiv of Cp(2)Co, respectively; further reduction of Pt(6)()(2+)() causes fast decomposition. The chloride derivatives [Pt(6)(mu-PBu(t)()(2))(4)(CO)(5)Cl]X, (Pt(6)()Cl(+)())X, and Pt(6)(mu-PBu(t)()(2))(4)(CO)(4)Cl(2), Pt(6)()Cl(2)(), observed as side-products in some electrochemical experiments, were prepared independently. The reaction leading to Pt(3)()(CO)(3)()(+)() has been analyzed with DFT methods, and identification of key intermediates allows outlining the reaction mechanism. Moreover, calculations for the whole series Pt(6)()(2+)() --> Pt(6)()(2)()(-)()( )()afford the otherwise unknown structures of the reduced derivatives. While the primary geometry is maintained by increasing electron population, the system undergoes progressive and concerted out-of-plane rotation of the four phosphido bridges (from D(2)(d)() to D(2) symmetry). The bonding at the central Pt(4) tetrahedron of the hexanuclear clusters (an example of 4c-2e(-) inorganic tetrahedral aromaticity in Pt(6)()(2+)()) is explained in simple MO terms.     

A general NMR method for rapid, efficient, and reliable biochemical screening

High-throughput screening is usually the method of drug-lead discovery. It is now well accepted that, for a functional assay, quality is more important than quantity. The ligand-based or protein-based NMR screening methodologies for detecting compounds binding to the macromolecular target of interest are now well established. A novel and sensitive NMR method for rapid, efficient, and reliable biochemical screening is presented. The method named 3-FABS (three fluorine atoms for biochemical screening) requires the labeling of the substrate with a CF(3) moiety and utilizes (19)F NMR spectroscopy for the detection of the starting and enzymatically modified substrates. The method allows for high-quality screening of large compound or natural product extract collections and for measuring their IC(50) values. Applications of this technique to the screening of inhibitors of the Ser/Thr kinase AKT1 and the protease trypsin are presented. In addition, an interesting application of 3-FABS to functional genomics is also presented.     

Fluorine-NMR competition binding experiments for high-throughput screening of large compound mixtures

High-throughput ligand-based NMR screening with competition binding experiments is extended to (19)F detection. Fluorine is a favorable nucleus for these experiments because of the significant contribution of the Chemical Shift Anisotropy (CSA) to the (19)F transverse relaxation of the ligand signal when bound to a macromolecular target. A low to moderate affinity ligand containing a fluorine atom is used as a reference molecule for the detection and characterization of new ligands. Titration NMR experiments with the selected reference compound are performed for finding the optimal set-up conditions for HTS and for deriving the binding constants of the identified NMR hits. Rapid HTS of large chemical mixtures and plant or fungi extracts against the receptor of interest is possible due to the high sensitivity of the (19)F nucleus and the absence of overlap with the signals of the mixtures to be screened. Finally, a novel approach for HTS using a reference molecule in combination with a control molecule is presented.     

(Bis(1,2,4-triazol-1-yl)methane)silver(I) phosphino complexes: structures and spectroscopic properties of mixed-ligand coordination polymers

Adducts of the ligand bis(1,2,4-triazol-1-yl)methane (tz(2)(CH(2))) of the form AgX:tz(2)(CH(2)):ER(3):MeCN (1:1:1:x) (X = NO(3), R = Ph, E = P, As, or Sb, x = 1 or 2; X = NO(2), ClO(4), O(3)SCF(3), E = P, R = Ph, x = 0, 1 or 2; X = NO(3), ClO(4), E = P, R = cy, x = 1; X = ClO(4), E = As, R = Ph, x = 2) and AgNO(3):tz(2)(CH(2)):P(o-tolyl)(3) (2:2:1) have been synthesized and characterized in the solid state and in solution by analyses, spectral (IR, far-IR, (1)H and (13)C NMR, ESI MS data) data, and conductivity measurements. In the one-dimensional polymers (characterized by X-ray studies) AgNO(3):tz(2)(CH(2)):PPh(3):CH(3)CN (1:1:1:1), AgClO(4):tz(2)(CH(2)):PPh(3):CH(3)CN (1:1:1:2), AgNO(3):tz(2)(CH(2)):AsPh(3): CH(3)CN (1:1:1:2), and AgNO(3):tz(2)(CH(2)):SbPh(3):CH(3)CN (1:1:1:2), the silver atom can be regarded as four-coordinate, the tz(2)(CH(2)) ligands behaving as bridging groups rather than chelates, with no pair of ligands being dominant, quasi-trans, in their interactions. The AgNO(3):tz(2)(CH(2)):P(o-tolyl)(3) (2:2:1) adduct is a two-dimensional polymer containing two independent silver atoms, one four-coordinated unsymmetrically by a pair of triazolyl rings, one P(o-tolyl)(3), and a unidentate nitrate and the second by a quasi-symmetrical O(2)NO chelate and a pair of equivalent triazolyl rings.     

Gold-catalyzed reactions of 2-alkynyl-phenylamines with alpha,beta-enones

[reaction: see text] The gold-catalyzed reaction of 2-alkynyl-phenylamines with alpha,beta-enones represents a new general one-pot entry into C-3-alkyl-indoles by sequential reactions. Gold-catalyzed sequential cyclization/alkylation, N-alkylation/cyclization, or N-alkylation/cyclization/alkylation reactions leading to different indoles can be directed by changing the 2-alkynyl-phenylamine 1/alpha,beta-enone 3 ratio and the reaction temperature. Unusual gold-catalyzed rearrangement reaction of indoles are observed at 140 degrees C. New gold-catalyzed formation of propargyl-alkyl ether under mild conditions and the hydration reaction of N-acetyl-2-ethynyl-phenylamine are reported.     

Size and persistence length of molecular bottle-brushes by Monte Carlo simulations

Single-chain simulations of densely branched comb polymers, or "molecular bottle-brushes" with side-chains attached to every (or every second) backbone monomer, were carried out by off-lattice Monte Carlo technique. A coarse-grained model, described by hard spheres connected by harmonic springs, was employed. Backbone lengths of up to 100 units were considered, and compared with the corresponding linear chains. The backbone molecular size was investigated as a function of its length at fixed arm size, and as a function of the arm size at fixed backbone length. The apparent swelling exponents obtained by a power-law fit were found to be larger than those for the corresponding linear polymers, indicative of stiffening of the comb backbone. The probability distribution function for the backbone end-to-end distance was also investigated for different backbone lengths and arm sizes. Analysis of this function yielded the critical exponents, which revealed an increase in the swelling exponent consistent with values found from the molecular size. The apparent persistence length of the backbone was also determined, and was found to increase with increasing branching density. Finally, the static structure factors of the whole bottle-brushes and of their backbones are discussed, which provides another consistent estimate of the swelling exponents.     

Group contributions to the infinite dilution partial molar volumes of alkanes, alcohols, and glycols in polar organic solvents

Densities of binary mixtures of polar organic solvents with alcohols were measured at 25‡C. The solvents studied were N,N-dimethylformamide, dimethylsulfoxide, and formamide while alcohols were butanol, pentanol, hexanol, and 1,4-butanediol. Density measurements of hydrocarbons (from pentane to dodecane and some heptane isomers) + N,N-dimethylformamide were also performed. From these data the apparent molar volumes of alcohols and hydrocarbons as functions of concentration were calculated. The standard partial molar volumes were obtained by extrapolation to infinite dilution and are discussed in terms of group contributions.     

Sensitivity improvement in 19F NMR-based screening experiments: theoretical considerations and experimental applications

NMR-based binding and functional screening performed with FAXS (fluorine chemical shift anisotropy and exchange for screening) and 3-FABS (three fluorine atoms for biochemical screening) represents a potential alternative approach to high-throughput screening for the identification of novel potential drug candidates. The major limitation of this method in its current status is its intrinsic low sensitivity that limits the number of tested compounds. One approach for overcoming this problem is the use of a cryogenically cooled (19)F probe that reduces the thermal noise in the receiver circuitry. Sensitivity improvement in the two screening techniques achieved with the novel cryogenic (19)F probe technology permits an increased throughput, detection of weaker binders and inhibitors (relevant in a fragment-based lead discovery program), detection of slow binders, and reduction in protein and substrate consumption. These aspects are analyzed with theoretical simulations and experimental quantitative performance evaluation. Application of 3-FABS combined with the cryogenic (19)F probe technology to rapid screening at very low enzyme concentrations and the current detection limits reached with this approach are also presented.     

Electrophilic cyclization of o-acetoxy- and o-benzyloxyalkynylpyridines: an easy entry into 2,3-disubstituted furopyridines

[reaction: see text] 2,3-Disubstituted furo[3,2-b]pyridines, 2,3-disubstituted furo[2,3-b]pyridines, and 2,3-disubstituted furo[2,3-c]pyridines are readily prepared under mild conditions via the palladium-catalyzed cross-coupling of 1-alkynes with o-iodoacetoxy- or o-iodobenzyloxypyridines, followed by electrophilic cyclization by I(2) or by PdCl(2) under a balloon of carbon monoxide.