The first example of a nitrile hydratase model complex that reversibly binds nitriles

Nitrile hydratase (NHase) is an iron-containing metalloenzyme that converts nitriles to amides. The mechanism by which this biochemical reaction occurs is unknown. One mechanism that has been proposed involves nucleophilic attack of an Fe-bound nitrile by water (or hydroxide). Reported herein is a five-coordinate model compound ([Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+)) containing Fe(III) in an environment resembling that of NHase, which reversibly binds a variety of nitriles, alcohols, amines, and thiocyanate. XAS shows that five-coordinate [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) reacts with both methanol and acetonitrile to afford a six-coordinate solvent-bound complex. Competitive binding studies demonstrate that MeCN preferentially binds over ROH, suggesting that nitriles would be capable of displacing the H(2)O coordinated to the iron site of NHase. Thermodynamic parameters were determined for acetonitrile (DeltaH = -6.2(+/-0.2) kcal/mol, DeltaS = -29.4(+/-0.8) eu), benzonitrile (-4.2(+/-0.6) kcal/mol, DeltaS = -18(+/-3) eu), and pyridine (DeltaH = -8(+/-1) kcal/mol, DeltaS = -41(+/-6) eu) binding to [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) using variable-temperature electronic absorption spectroscopy. Ligand exchange kinetics were examined for acetonitrile, iso-propylnitrile, benzonitrile, and 4-tert-butylpyridine using (13)C NMR line-broadening analysis, at a variety of temperatures. Activation parameters for ligand exchange were determined to be DeltaH(+ +) = 7.1(+/-0.8) kcal/mol, DeltaS(+ +) = -10(+/-1) eu (acetonitrile), DeltaH(+ +) = 5.4(+/-0.6) kcal/mol, DeltaS(+ +) = -17(+/-2) eu (iso-propionitrile), DeltaH(+ +) = 4.9(+/-0.8) kcal/mol, DeltaS(+ +) = -20(+/-3) eu (benzonitrile), and DeltaH(+ +) = 4.7(+/-1.4) kcal/mol DeltaS(+ +) = -18(+/-2) eu (4-tert-butylpyridine). The thermodynamic parameters for pyridine binding to a related complex, [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) (DeltaH = -5.9(+/-0.8) kcal/mol, DeltaS = -24(+/-3) eu), are also reported, as well as kinetic parameters for 4-tert-butylpyridine exchange (DeltaH(+ +) = 3.1(+/-0.8) kcal/mol, DeltaS(+ +) = -25(+/-3) eu). These data show for the first time that, when it is contained in a ligand environment similar to that of NHase, Fe(III) is capable of forming a stable complex with nitriles. Also, the rates of ligand exchange demonstrate that low-spin Fe(III) in this ligand environment is more labile than expected. Furthermore, comparison of [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) and [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) demonstrates how minor distortions induced by ligand constraints can dramatically alter the reactivity of a metal complex.     

Natriumkomplexe mit Salicylideniminen: Synthesen,Strukturen, CO2‐Aufnahme und Carboxylierung von 2‐Fluorpropiophenon bzw. Estronmethylether

Chiral salicylidenphenethylamines (R)‐HA or (S)‐HA , 2‐salicylidenfurfuryl‐imines HB , and 2‐salicylidenaminoethanol HC react with sodium hydride or sodium hexamethyldisilylamide to form the sodium complexes [Na(R)‐A] ₄ · 0,5 Et ₂ , [Na(S)‐A] ₄ · 0,5 Et ₂ O (1) , [NaB] ₄ · 0,5 Ph‐Me (2) and [(dme)NaC] ₄ (3) . In the presence of 18‐crown‐6 the complex [Na(18‐crown‐6)(thf) ₂ ] ₂ [Na ₂ (C)] ₄ · THF (4) can also be isolated. The crystal structure analyses of both 1 and 2 show that heterocubane structures with a Na₄O₄ frame work are formed. Additionally, the imine nitrogen atom is bonded at the Na atom which has the coordination number 4 in 1 . Additional coordination of the furfuryl oxygen atom results in the coordination number five for the sodium atom in 2 . In 3 which is also a tetramer, two Na₂O₂ units are connected via two imino‐ethanol bridges Na(1)‐N(=CH‐phenolat)‐CH₂CH₂‐OH‐Na(2A). The crystal structure analysis displays that 4 is an ionic compound consisting of two [(thf)₂Na(18‐crown‐6)]⁺ cations and the dinuclear dianion [Na ₂ (C) ₄ ] ^2? . Both 1 and 2 are carboxylation reagents which transfer CO₂ to 2‐fluoropropiophenone. 1 is more active than 2 , but 3 and 4 are inactive.     

Rare Events in Random Geometric Graphs

This work introduces and compares approaches for estimating rare-event probabilities related to the number of edges in the random geometric graph on a Poisson point process. In the one-dimensional setting, we derive closed-form expressions for a variety of conditional probabilities related to the number of edges in the random geometric graph and develop conditional Monte Carlo algorithms for estimating rare-event probabilities on this basis. We prove rigorously a reduction in variance when compared to the crude Monte Carlo estimators and illustrate the magnitude of the improvements in a simulation study. In higher dimensions, we use conditional Monte Carlo to remove the fluctuations in the estimator coming from the randomness in the Poisson number of nodes. Finally, building on conceptual insights from large-deviations theory, we illustrate that importance sampling using a Gibbsian point process can further substantially reduce the estimation variance.

     

Determination of pharmaceuticals, iodinated contrast media and musk fragrances in sludge by LC/tandem MS and GC/MS

Analytical methods have been developed that allow for the determination of antiphlogistics, lipid regulators, the antiepileptic carbamazepine, cytostatic agents, the psychiatric drug diazepam and iodinated contrast media (ICM) as well as two major polycyclic musk fragrances HHCB (galaxolide) and AHTN (tonalide) in activated and digested sludge. The procedures consist of ultrasonic solvent extraction (USE) using methanol/acetone or pressurized liquid extraction (PLE) using 100% methanol. Clean-up was performed with C18ec material and silica gel followed by LC tandem MS (electrospray or atmospheric pressure chemical ionization) detection for pharmaceuticals and iodinated contrast media as well as GC/MS in the SIM mode for musk fragrances. Absolute recoveries from spiked activated sludge in general ranged from 88+/-4 to 119+/-20% for ICM and were 78+/-15 and 87+/-10% for the AHTN and HHCB, respectively. For the pharmaceuticals, absolute recoveries in activated sludge ranged between 43 and 78%. Subsequently, compensation of losses was carried out by using surrogate standards (acidic pharmaceuticals: fenoprop, neutral pharmaceuticals: dihydro-carbamazepine, musk fragrances: AHTN-D3). With one exception the recoveries were also adequate in digested sludge ranging from 43% to 120%.     

Atomistic Simulation Study of Calcium,Phosphate and Fluoride Ion Association to the Teleopeptide‐Tails of Collagen – Initial Steps to Biomineral Formation

The attachment of single ions to putative adsorption sites in the tails of collagen fibers is investigated by means of molecular dynamics simulations and discussed with respect to the very early steps of apatite/collagen biomineral formation. Our studies clearly demonstrate an increased flexibility of the tails of the triple‐helical collagen protein. Apart from the termini of the backbone, several side chains were also observed to be freely accessible to ion attachment from aqueous solution. The teleopeptide was systematically scanned for suitable adsorption sites for calcium, phosphate and fluoride ions. Association of these ions was then explored from potential of mean force calculations. The resulting energy profiles reveal a variety of favorable protein‐ion bonds and hint at the suitability of the collagen tails to promote apatite aggregation.     

Magnetic and Electrical Properties, Eu Mössbauer Spectroscopy, and Chemical Bonding of REAgMg (RE=La, Ce, Eu, Yb) and EuAuMg

Single-phase samples of REAgMg (RE=La, Ce, Eu, Yb) and EuAuMg were prepared by reacting the elements in sealed tantalum tubes in a high-frequency furnace. LaAgMg and CeAgMg adopt the hexagonal ZrNiAl-type structure, while EuAgMg, YbAgMg, and EuAuMg crystallize with the orthorhombic TiNiSi type. Chemical bonding was exemplarily investigatedfor EuAgMg and EuAuMg on the basis of TB-LMTO-ASAcalculations. Magnetic susceptibility measurements indicatePauli paramagnetism for LaAgMg and YbAgMg with room-temperature susceptibilities of 2.4(1)×10⁻⁹ and 1.5(1)×10⁻⁹ m³/mol, respectively. CeAgMg remains paramagnetic down to 2 K. The experimental magnetic moment of 2.52(2) μ_B/Ce above 50 K is compatible with trivalent cerium. EuAgMg and EuAuMg are paramagnetic above 50 K with experimentalmagnetic moments of 7.99(5) μ_B/Eu for the silver and 7.80(5) μ_B/Eu for the gold compound, indicating divalent europium. Ferromagnetic ordering is detected at T_C=22.0(3) K (EuAgMg) and T_C=36.5(5) K (EuAuMg). At 4.2 K and 5 T the saturation magnetizations are 7.1(1) and 7.3(1) μ_B/Eu for EuAgMg and EuAuMg, respectively. According to the very small hysteresis, EuAgMg and EuAuMg may be classified as soft ferromagnets. All compounds are metallic conductors. For EuAgMg and EuAuMg freezing of spin-disorder scattering is observed below T_C. At 78 K ¹⁵¹Eu Mössbauer spectra show isomer shifts of −9.00(4) and −8.72(8) mm/s for EuAgMg and EuAuMg, respectively. Full magnetic hyperfine field splitting is detected at 4.2 K with hyperfine fields of 17.4(1) and 18.3(2) T at the europium nuclei of EuAgMg and EuAuMg.     

Versatile organic (fullerene)-inorganic (CdTe nanoparticle) nanoensembles

Novel organic (positively charged fullerene)-inorganic (negatively charged CdTe nanoparticle) nanoensembles were devised through electrostatic interactions and probed as versatile donor-acceptor hybrids. Photoirradiation of their homogeneous solutions, containing the electrostatically packed components, let to very long-lived (1.3 ms) charge separated states.     

Biologically active compounds through catalysis: efficient synthesis of N-(heteroarylcarbonyl)-N'-(arylalkyl)piperazines

A practical route for the synthesis of new biologically active 5-HT(2 A) receptor antagonists has been developed. In only three catalytic steps, this class of central nervous system (CNS) active compounds can be synthesized efficiently with high diversity. As the initial step, an anti-Markovnikov addition of amines to styrenes provides an easy route to N-(arylalkyl)piperazines, which constitute the core structure of the active molecules. Here, base-catalyzed hydroamination reactions of styrenes with benzylated piperazine proceeded in high yield even at room temperature. After catalytic debenzylation, the free amines were successfully carbonylated with different aromatic and heteroaromatic halides and carbon monoxide to yield the desired compounds in good to excellent yields. The two key reactions, base-catalyzed hydroamination of styrenes and palladium-catalyzed aminocarbonylation of haloarenes/heterocycles, showed tolerance towards various functional groups, thereby demonstrating the potential to synthesize a wide variety of new derivatives of this promising class of pharmaceuticals.     

Crystal structures, electronic properties, and pressure-induced superconductivity of the tetrahedral cluster compounds GaNb(4)S(8), GaNb(4)Se(8), and GaTa(4)Se(8)

The crystal structures of the tetrahedral cluster compounds GaNb(4)S(8) and GaTa(4)Se(8) were determined by single-crystal X-ray diffraction. They crystallize in the cubic GaMo(4)S(8) structure type (F3m), which can be derived from the spinel type by shifting the metal atoms off the centers of the chalcogen octahedra along [111]. Electrical resistivity and magnetic susceptibility measurements show that the electronic conduction originates from hopping of localized unpaired electrons (S = (1)/(2)) among widely separated Nb(4) or Ta(4) clusters, and thus these materials represent a new class of Mott insulators. Under high pressure we find that GaNb(4)S(8) undergoes a transition from the Mott insulating to a superconducting state with T(C) up to 4 K at 23 GPa, similar to GaNb(4)Se(8) and GaTa(4)Se(8). High-pressure single-crystal X-ray studies of GaTa(4)Se(8) reveal that the superconducting transition is connected with a gradual decrease of the octahedral distortion with increasing pressure. DFT band structure calculations show that weakly coupled cluster orbitals are responsible for a high density of states at the Fermi level. The correct insulating magnetic ground state for GaNb(4)S(8) with mu(eff) = 1.73 mu(B) is for the first time achieved by the LDA+U method using U = 6 eV and rhombohedral symmetry.     

Asymmetric synthesis of β-substituted Baylis-Hillman products via lithium amide conjugate addition

A three-step protocol for the asymmetric synthesis of a range of β-substituted Baylis-Hillman products has been developed. This procedure involves the diastereoselective conjugate addition of lithium (R)-N-methyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester to generate an N-protected β-amino ester in high de. Subsequent asymmetric aldol reaction via deprotonation with LDA, transmetallation with B(OMe)₃ and addition of an aldehyde gives a range of syn-aldol products in moderate to high de. Purification of the syn-aldol products to homogeneity followed by tandem N-oxidation and Cope elimination gives the desired β-substituted Baylis-Hillman products in good yield and high de and ee.