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Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with “any event” was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2 was associated with higher levels of 17-hydroxy exemestane (P = 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20–1.01; P = 0.05) compared with homozygote UGT2B17 wt. The CYP19A1 rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P = 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P

Little is known about the regional extent and variability of nitrate from atmospheric deposition that is transported to streams without biological processing in forests. We measured water chemistry and isotopic tracers (δ18O and δ15N) of nitrate sources across the Northern Forest Region of the U.S. and Canada and reanalyzed data from other studies to determine when, where, and how unprocessed atmospheric nitrate was transported in catchments. These inputs were more widespread and numerous than commonly recognized, but with high spatial and temporal variability. Only 6 of 32 streams had high fractions (>20%) of unprocessed atmospheric nitrate during baseflow. Seventeen had high fractions during stormflow or snowmelt, which corresponded to large fractions in near-surface soil waters or groundwaters, but not deep groundwater. The remaining 10 streams occasionally had some (

A mononuclear W(IV) bis-dithiolene complex stabilized by an oxo ligand shows a reductive reactivity toward CO2, from which formate and a dinuclear W(V) complex are generated. An unusual structural rearrangement was observed during the reaction. Structural and spectroscopic characterization for a novel triply bridged dinuclear W(V) complex is reported.

Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase. We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy. Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E−11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio. These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.

Crude glycerol is a low value by-product of the biodiesel industry, and its use as an alkaline catalyst component offers a cost-lowering strategy for sustainable fuel production. Sodium glyceroxide can be used to generate methoxide ions in situ, and the latter act as catalysts for the transesterification of triglycerides to fatty acid methyl esters (biodiesel, or FAMEs). Catalytic formulations of sodium glyceroxide were prepared from glycerol, methanol and NaOH, characterized by X-ray diffraction, and used for rapid transesterification of canola oil into biodiesel. The kinetics of the reaction using 6 and 9 M equivalents of methanol and 0.5 wt.% and 1.0 wt.% catalyst loading were studied by 1H NMR spectroscopy. Catalyst formulations prepared from crude glycerol performed transesterification reactions in methanol at a rate comparable to those observed for sodium hydroxide. Analogous to methoxide-catalyzed transesterifications, the reactions using glyceroxide appeared to be rate-limited by mass transfer. The relative viscosities of glyceroxide formulations prepared in methanol are also presented, and show an inverse correlation between viscosity and increasing concentration, a trend characteristic of ionic glycerol solutions.

A new Au22 nanocluster, protected by bis(2-diphenyl-phosphino)ethyl ether (dppee or C28 H28 OP2 ) ligand, has been synthsized and purified with high yield. Electrospray mass spectrometry shows that the new cluster has a formula of Au22 (dppee)7 , containing 22 gold atoms and seven dppee ligands. The cluster is found to be stable as a solid, but metastable in solution. The new cluster has been characterized by UV-Vis-NIR absorption spectroscopy, collision-induced dissociation, and (31) P-NMR. The properties of the new cluster have been compared with the previous Au22 (dppo)6 nanocluster (dppo = 1,8-bis(diphenyl-phosphino)octane or C32 H36 P2 ), which contains two fused Au11 units. All the experimental data indicate that the new Au22 (dppee)7 cluster is different from the previously known Au22 (dppo)6 cluster and represents a new Au22 core, which contains most likely one Au11 motif with several Au2 (dppee) or Au(dppee) units. The Au22 (dppee)7 cluster provides a new example of the ligand effects on the nuclearity and structural polymorphism of phosphine-protected atom-precise gold nanoclusters.

A family of low-valent molybdenum complexes supported by the pincer ligand PNMeP (PNMeP = MeN(CH2CH2PPh2)2) was prepared and characterized, including (PNMeP)Mo(C2H4)2, which contains an agostic interaction between the metal and the N-methyl substituent. This β-agostic C–H bond was cleaved by molybdenum and produced a cyclometalated molybdenum formate complex, (κ4-PNMeP)Mo(C2H4)(κ2-O2CH), upon exposure to CO2. This species serves as a promotor of CO2 hydrogenation to formate under basic conditions, a rare transformation for group VI metals. The performance of the precatalyst was enhanced with the addition of Lewis acid salts.

We reported the first systematic study of the solid-state aldol reactions of solvated and unsolvated lithium pinacolone enolate with a variety of solid aromatic aldehydes utilizing a mortar and pestle condition in comparison with the simple ball milling condition or tetrahydrofuran (THF) solution condition. In solution, the reactions are highly-selective with the aldol condensation product at room temperature. Under the condition of mortar and pestle, the reactions with unsolvated lithium pinacolone enolate showed the mixture of aldol condensation product and aldol addition product at room temperature. With the usage of solvated lithium pinacolone enolate, higher yields for most substrates were obtained. Furthermore, repeating the reactions under a simple ball billing condition with no other precautions at room temperature, we achieved high selectivity and yield of products for all substrates, indicating the powerful ability and the utility of solid-state, mechanochemical aldol reaction conditions.

We report extension of the D-FW analysis using referenced (2)H DOSY. This technique was developed in response to limitations due to peak overlay in (1)H DOSY spectra. We find a corresponding linear relationship (R(2)0.99) between log D and log FW as the basis of the D-FW analysis. The solution-state structure of THF solvated lithium diisopropyl amide (LDA) in hydrocarbon solvent was chosen to demonstrate the reliability of the methodology. We observe an equilibrium between monosolvated and disolvated dimeric LDA complexes at room temperature. Additionally we demonstrate the application of the (2)H D-FW analysis using a compound with an exchangeable proton that is readily labeled with (2)H. Hence, the (2)H DOSY D-FW analysis is shown to provide results consistent with the (1)H DOSY method, thereby greatly extending the applicability of the D-FW analysis.

We determined hormone concentrations (estradiol [E2], estrone [E1], estrone conjugates [E1-C], androstenedione [A], testosterone [T]) before and on anastrozole therapy where we also determined plasma concentrations of anastrozole and its metabolites.Postmenopausal women who were to receive adjuvant anastrozole for resected early breast cancer were studied. Pretreatment, blood samples were obtained for the acquisition of DNA and for plasma hormone measurements (E2, E1, E1-C, A, and T). A second blood draw was obtained at least 4 weeks after starting anastrozole for hormone, anastrozole and metabolite measurements. For hormone assays, a validated bioanalytical method using gas chromatography negative ionization tandem mass spectrometry was used. Anastrozole and metabolite assays involved extraction of plasma followed by LC/MS/MS assays.649 patients were evaluable. Pretreatment and during anastrozole, there was large inter-individual variability in E2, E1, and E1-C as well as anastrozole and anastrozole metabolite concentrations. E2 and E1 concentrations were below the lower limits of quantitation in 79% and 70%, respectively, of patients on anastrozole therapy, but those with reliable concentrations had a broad range (0.627-234.0 pg/mL, 1.562-183.2 pg/mL, respectively). Considering E2, 8.9% had the same or higher concentration relative to baseline while on anastrozole, documented by the presence of drug.We demonstrated large inter-individual variability in anastrozole and anastrozole metabolite concentrations as well as E1, E2, E1-C, A, and T concentrations before and while on anastrozole. These findings suggest that the standard 1mg daily dose of anastrozole is not optimal for a substantial proportion of women with breast cancer.

The analyses of endogenous substances as biomarkers presents challenges that are distinctly different from the analyses of drugs or other xenobiotic substances. This is particularly true for estrogens. When no matrix is available which does not contain some level of the biomarker of interest, specificity cannot be demonstrated. Therefore it cannot be known whether the analyte signal includes a response from another substance. This uncertainty is increased by the fact that biomarkers are often created as part of a complex biosynthetic process that also creates a large number of substances with very similar structures and sometimes the same mass. Because of this, the two most powerful selectivity tools in the analysis of drugs, mass selective detection and MS/MS, are often rendered ineffective. The only remaining selectivity tool is chromatography and as will be demonstrated these separations can be very challenging. Failure to achieve specificity is perhaps the leading cause for inaccuracy of biomarker data and inter-laboratory variability.

The biochemical mechanism for the formation of the C-P-C bond sequence found in l-phosphinothricin, a natural product with antibiotic and herbicidal activity, remains unclear. To obtain further insight into the catalytic mechanism of PhpK, the P-methyltransferase responsible for the formation of the second C-P bond in l-phosphinothricin, we utilized a combination of stable isotopes and two-dimensional nuclear magnetic resonance spectroscopy. Exploiting the newly emerged Bruker QCI probe (Bruker Corp.), we specifically designed and ran a C-13-P-31 multiple quantum H-1-C-13-P-31 (HCP) experiment in H-1-P-31 two-dimensional mode directly on a PhpK-catalyzed reaction mixture using (CH3)-C-13-labeled methylcobalamin as the methyl group donor. This method is particularly advantageous because minimal sample purification is needed to maximize product visualization. The observed 3:1:1:3 multiplet specifically and unequivocally illustrates direct bond formation between (CH3)-C-13 and P-31. Related nuclear magnetic resonance experiments based upon these principles may be designed for the study of enzymatic and/or synthetic chemical reaction mechanisms. Copyright (c) 2015 John Wiley & Sons, Ltd.

A family of iron(II) carbonyl hydride complexes supported by either a bifunctional PNP ligand containing a secondary amine, or a PNP ligand with a tertiary amine that prevents metal–ligand cooperativity, were found to promote the catalytic hydrogenation of CO2 to formate in the presence of Bronsted base. In both cases a remarkable enhancement in catalytic activity was observed upon the addition of Lewis acid (LA) co-catalysts. For the secondary amine supported system, turnover numbers of approximately 9000 for formate production were achieved, while for catalysts supported by the tertiary amine ligand, nearly 60 000 turnovers were observed; the highest activity reported for an earth abundant catalyst to date. The LA co-catalysts raise the turnover number by more than an order of magnitude in each case. In the secondary amine system, mechanistic investigations implicated the LA in disrupting an intramolecular hydrogen bond between the PNP ligand N–H moiety and the carbonyl oxygen of a formate ligand in the catalytic resting state. This destabilization of the iron-bound formate accelerates product extrusion, the rate-limiting step in catalysis. In systems supported by ligands with the tertiary amine, it was demonstrated that the LA enhancement originates from cation assisted substitution of formate for dihydrogen during the slow step in catalysis.

A 3-yr study was conducted on a corn field in central Illinois, USA, to understand the fate and effects of an insecticidal formulation containing the active ingredients phostebupirim and cyfluthrin. The objectives were to determine the best tillage practice (conventional vs conservation tillage) in terms of grain yields and potential environmental risk, to assess insecticidal exposure using concentrations measured in soil and runoff water and sediments, to compare measured insecticidal concentrations with predicted concentrations from selected risk assessment exposure models, and to calculate toxicity benchmarks from laboratory bioassays performed on reference aquatic and terrestrial nontarget organisms, using individual active ingredients and the formulation. Corn grain yields were not significantly different based on tillage treatment. Similarly, field concentrations of insecticides were not significantly (p > 0.05) different in strip tillage versus conventional tillage, suggesting that neither of the tillage systems would enable greater environmental risk from the insecticidal formulation. Risk quotients were calculated from field concentrations and toxicity data to determine potential risk to nontarget species. The insecticidal formulation used at the recommended rate resulted in soil, sediment, and water concentrations that were potentially harmful to aquatic and terrestrial invertebrates, if exposure occurred, with risk quotients up to 34. Environ Toxicol Chem 2015;34:197–207. © 2014 SETAC

Solution characterizations and ligand binding constants were determined for n-butyllithium in hydrocarbon and ethereal solvents using diffusion-ordered NMR. In hydrocarbon solvents, n-butyllithium exists primarily as an octamer at −40 °C and deaggregates to a hexamer when the temperature is increased. In the presence of THF or diethyl ether, n-butyllithium exists predominantly as a tetra-solvated tetramer and deaggregates to a tetra-solvated dimer in the presence of a large excess or neat THF. The ligand binding constants for the tetra-solvated tetramers were measured using 1H NMR/DOSY titration.

N-acetylglucosaminidases (GlcNAcases) play an important role in the remodeling and recycling of bacterial peptidoglycan by degrading the polysaccharide backbone. Genetic deletions of autolysins can impair cell division and growth, suggesting an opportunity for using small molecule autolysin inhibitors as both tools for studying the chemical biology of autolysins and also serving as anti-bacterial agents. We report here the synthesis and evaluation of a panel of diamides that inhibit the growth of Bacillus subtilis. Two compounds, fgkc (5) and fgka (21), were found to be potent inhibitors (MIC 3.8 ± 1.0 and 21.3 ± 0.1 µM respectively). These compounds inhibit the B. subtilis family 73 glycosyl hydrolase LytG, an exo GlcNAcase. Phenotypic analysis of fgkc (21)-treated cells demonstrate a propensity for cells to form linked chains, suggesting impaired cell growth and division.

The crosstalk between two biologically important signaling molecules, nitric oxide (NO) and hydrogen sulfide (H2S), proceeds via elusive mechanism(s). Herein we report the formation of H2S by the action of NO on synthetic [2Fe-2S] clusters when the reaction environment is capable of providing a formal H(•) (e(-)/H(+)). Nitrosylation of (NEt4)2[Fe2S2(SPh)4] (1) in the presence of PhSH or (t)Bu3PhOH results in the formation of (NEt4)[Fe(NO)2(SPh)2] (2) and H2S with the concomitant generation of PhSSPh or (t)Bu3PhO(•). The amount of H2S generated is dependent on the electronic environment of the [2Fe-2S] cluster as well as the type of H(•) donor. Employment of clusters with electron-donating groups or H(•) donors from thiols leads to a larger amount of H2S evolution. The 1/NO reaction in the presence of PhSH exhibits biphasic decay kinetics with no deuterium kinetic isotope effect upon PhSD substitution. However, the rates of decay increase significantly with the use of 4-MeO-PhSH or 4-Me-PhSH in place of PhSH. These results provide the first chemical evidence to suggest that [Fe-S] clusters are likely to be a site for the crosstalk between NO and H2S in biology.

Four different chiral diamino diethers synthesized from N-isopropyl valinol or N-isopropyl alaninol were lithiated with n-butyllithium in tetrahydrofuran or diethyl ether. Crystal structures of the dilithiated diamino diethers were determined by X-ray diffraction. Three dilithiated diamino diethers including (2S,2'S)-1,1'-(butane-1,4-diylbis(oxy))bis(N-isopropylpropan-2-amine) 7, (2S,2'S)-1,1'-(pentane-1,5-diylbis(oxy))bis(N-isopropylpropan-2-amine) 8, and (2S,2'S)-1,1'-(heptane-1,7-diylbis(oxy))bis(N-isopropyl-3-methylbutan-2-amine) 9 are dimers, whereas dilithiated (2S,2'S)-1,1'-(pentane-1,5-diylbis(oxy))bis(N-isopropyl-3-methylbutan-2-amine) 10 is a monomer. The lithium atoms in all crystal structures adopt a nonequivalent coordination protocol and exist in two different environments in which one of the lithium atoms is tetra-coordinated while the other one is tri-coordinated. The solution structures of the dilithiated diamino diethers are also characterized by a variety of NMR experiments including diffusion-ordered NMR spectroscopy (DOSY) with diffusion coefficient-formula (D-FW) weight correlation analyses and other one- and two-dimensional NMR techniques.

A series of zerovalent molybdenum complexes bearing triphosphine ligands, [Ar2PCH2CH2]2PPh, have been synthesized and evaluated for reductive functionalization of CO2 with ethylene. The ability to form dimeric triphosphine molybdenum(II) acrylate hydride species from CO2-ethylene coupling was found to be highly sensitive to steric encumbrance on the phosphine aryl substituents. Trapping of triphosphine molybdenum(II) acrylate hydride species using triphenylphosphine afforded isolable monomeric CO2 functionalization products with all ancillary ligands studied. Kinetic analysis of the acrylate formation reaction revealed a first-order dependence on molybdenum, but no influence from CO2 pressure or the triphenylphosphine trap. Systematic attenuation of steric and electronic features of the triphosphine ligands showed a strong CO2 functionalization rate influence for ligand size with [(3,5-tBu-C6H3)2PCH2CH2]2PPh coupling nearly four times slower than with [(3,5-Me-C6H3)2PCH2CH2]2PPh. A considerably milder ele...

The catalytic conversion of carbon dioxide and olefins into acrylates has been a long standing target, because society attempts to synthesize commodity chemicals in a more economical and sustainable fashion. Although nickel complexes have been known to successfully couple CO2 and ethylene for decades, a key β-hydride elimination step has proven a major obstacle to the development of a catalytic process. Recent studies have shown that Lewis acid additives can be used to create a lower-energy pathway for β-hydride elimination and facilitate a low number of catalytic turnovers. However, the exact manner, in which the Lewis acid promotes β-hydride elimination remains to be elucidated. Herein, we describe the kinetic and thermodynamic role that commercially relevant and weakly Lewis acidic sodium salts play in promoting β-hydride elimination from nickelalactones synthesized from CO2 and ethylene. This process is compared to a non-Lewis acid promoted pathway, and DFT calculations were used to identify differences between the two systems. The sodium-free isomerization reaction gave a rare CO2 -derived β-nickelalactone complex, which was structurally characterized.

Crystal structure determination of lithiated N-methylaniline with a variety of ligands, including tetrahydrofuran, methyltetrahydrofuran, trans-2,5-dimethyltetrahydrofuran, dimethoxyethane, tetrahydropyran and N,N-diethylpropionamide, reveals a common Li–N–Li–N four-membered-ring dimeric structure motif. A progression of solvation from tetrasolvated dimer (PhNMeLi·S2)2 through trisolvated dimer to disolvated dimer (PhNMeLi·S)2 was observed by increasing the steric hindrance of the ligand. Solid-state structures of several other lithium N-alkylanilides solvated by tetrahydrofuan are also reported. When the methyl group of N-methylaniline is replaced by an isopropyl or a phenyl group, trisolvated monomers are formed instead of dimers. Interestingly, the solid-state structure of lithiated N-isobutylaniline in tetrahydrofuran is a trisolvated dimer while that of lithium N-neopentylanilide is a disolvated dimer.

The western segment of hygrocins A–B has been synthesized through the coupling of a chiral C5–C13 synthon with the sterically demanding hexasubstituted naphthalenic core. The C5–C13 chiral fragment has been assembled via a stereoselective Johnson orthoester rearrangement of an optically pure allylic alcohol derived from d-glucose. Our studies lay the platform for the determination of the absolute configuration of the unassigned C8-stereocenter of the title compounds in addition to the completion of the total synthesis of the unique ansamacrolides hygrocins A and B.

Soil bacteria display their self-defense as an essential disposition to withstand unfavorable rhizobial conditions. They employ those mechanisms through catabolic and/or anabolic metabolisms such as detoxification of xenobiotis or biosynthesis of nutrients de novo. In this study, newly isolated soil bacterium Arthrobacter nicotianae strain PR was identified, characterized and bioinformatically examined to reveal its synthetase gene. The bacterial genomic DNA was probed in PCR with degenerate synthetase primers. The amplified PCR product was cloned and sequenced. The gene and protein sequence analysis was made using MEGA 4 software and BLASTX search of NCBI-linked protein databases. The conserved amino acid residues revealed the match to aldo-keto reductase (AKR). The multiple sequence-data alignments analysis confirmed the AKR, and multiple phylogeneitic data analysis confirmed its relationship with other bacteria. This enzyme, AKR, belongs to a growing oxidoreductase superfamily and metabolizes a wide range of substrates, including aliphatic aldehydes, monosaccharides, steroids, prostaglandins, and xenobiotics. Our phylogenetic study reveals that this protein is potentially vital in assisting bacteria withstand unfavorable soil environmental condition. Since AKR found in many bacteria and eukaryotes like mammals, amphibians etc, the phylogenetic relationship between our soil isolate and other bacteria was significant as it revealed a distant relationship with A. aurescens.

We report the synthesis and structure determination of a new Au22 nanocluster coordinated by six bidentate diphosphine ligands: 1,8-bis(diphenylphosphino) octane (L(8) for short). Single crystal X-ray crystallography and electrospray ionization mass spectrometry show that the cluster assembly is neutral and can be formulated as Au22(L(8))6. The Au22 core consists of two Au11 units clipped together by four L(8) ligands, while the additional two ligands coordinate to each Au11 unit in a bidentate fashion. Eight gold atoms at the interface of the two Au11 units are not coordinated by any ligands. Four short gold-gold distances (2.64-2.65 Å) are observed at the interface of the two Au11 clusters as a result of the clamping force of the four clipping ligands and strong electronic interactions. The eight uncoordinated surface gold atoms in the Au22(L(8))6 nanocluster are unprecedented in atom-precise gold nanoparticles and can be considered as potential in situ active sites for catalysis.

We report the development of isotopic-labeled (13)C diffusion-ordered NMR spectroscopy (DOSY) NMR with diffusion coefficient-formula weight (D-FW) analysis and its application in characterizing the aggregation state of methyllithium aggregates and complexes with several widely used diamines. Commercially available (13)C-labeled benzene and several easily synthesized (13)C-labeled compounds using (13)C-labeled iodomethane as the isotopic source are developed as internal references for diffusion-formula weight analysis (D-FW). The technique greatly expands the applicability of DOSY D-FW analysis to a much wider variety of compounds because of isotopic labeling. These results reveal that methyllithium exists as a tetrasolvated tetramer in diethyl ether and exclusively as bis-solvated dimers with chelating diamines.

A family of new iridium phosphine–sulfonate complexes based on 2-dicyclohexylphosphino-4-benzenesulfonic acid was synthesized and characterized. An iridium(I) phosphine–sulfonate cyclooctadiene species was prepared from transmetalation of a silver salt of the phosphine–sulfonate ligand and iridium(I) cyclooctadiene chloride dimer. This diolefin iridium complex was found to be a functional precatalyst for cyclopentene hydrogenation. A corresponding iridium(I) phosphine–sulfonate dicarbonyl species was prepared by ligand substitution using carbon monoxide. Analysis by infrared spectroscopy established this metal–ligand platform as a relatively electron poor coordination environment. The iridium(I) phosphine–sulfonate cyclooctadiene species was further utilized as a precursor for the synthesis of two iridium(III) phosphine–sulfonate hydride compounds by treatment with strong acids.

The crystal structure of a mixed aggregate containing lithiated (S)-N-ethyl-3-methyl-1-(triisopropylsilyloxy)butan-2-amine derived from (S)-valinol and cyclopentyllithium is determined by X-ray diffraction. The mixed aggregate adopts a ladder structure in the solid state. The ladder-type mixed aggregate is also the major species in a toluene-d8 solution containing an approximately 1:1 molar ratio of the lithiated chiral amide to cyclopentyllithium. A variety of NMR experiments including diffusion-ordered NMR spectroscopy (DOSY) with diffusion coefficient-formula (D-FW) weight correlation analyses and other one- and two-dimensional NMR techniques allowed us to characterize the complex in solution. Solution state structures of the mixed aggregates of n-butyl, sec-butyllithium, isopropyllithium with lithiated (S)-N-ethyl-3-methyl-1-(triisopropylsilyloxy)butan-2-amine are also reported. Identical dimeric, ladder-type, mixed aggregates are the major species at a stoichiometric ratio of 1:1 lithium chiral amide to alkyllithium in toluene-d8 solution for all of the different alkyllithium reagents.

The solid-state structures of unsolvated, hexameric cyclopentyllithium and tetrameric cyclopentyllithium tetrahydrofuran solvate were determined by single-crystal X-ray diffraction. Cyclopentyllithium easily crystallized in hydrocarbon solvents. Solution-state structural analyses of cyclopentyllithium and cyclopentyllithium-tetrahydrofuran complexes in toluene-d8 were also carried out by diffusion-ordered NMR spectroscopy with diffusion coefficient-formula weight correlation analyses and other one- and two-dimensional NMR techniques. The solution-state studies suggest that unsolvated cyclopentyllithium exists as hexamer and tetramer equilibrating with each other. Upon solvation with tetrahydrofuran, cyclopentyllithium exists mostly as a tetrahydrofuran tetrasolvated tetramer.

Solution-state characterization of sec-butyllithium in [D8]toluene was conducted by utilizing a variety of NMR spectroscopic experiments including diffusion-ordered NMR spectroscopy (DOSY) with diffusion-coefficient–formula-weight correlation analyses and other one- and two-dimensional NMR spectroscopic techniques. These results suggest that sec-butyllithium exists primarily as a tetramer/hexamer mixture in hydrocarbon solvents. However, the presence of roughly 2–5 % (by mol ratio) lithium sec-butoxide in both commercially available and laboratory-synthesized sec-butyllithium solutions due to the reaction with adventitious dioxygen will lead to the formation of a 1:5 sec-butoxide/sec-butyllithium mixed hexamer. A sec-butoxide/sec-butyllithium mixed octamer will emerge when the proportion of butoxide to butyllithium increases.

The molybdenum tetrahydride species (Triphos)MoH4PPh3 (Triphos = PhP(CH2CH2PPh2)2) generated from sodium triethylborohydride addition to (Triphos)MoCl3 was found to promote CO2 functionalization to afford acrylate, propionate, and formate species. The formation of (Triphos)MoH4PPh3 occurs via a (Triphos)Mo(H)Cl(PPh3) intermediate followed by dismutation of an unobserved six-coordinate molybdenum(II) dihydride complex. Addition of dihydrogen to the dismuation product mixture affords a nearly quantitative yield of (Triphos)MoH4PPh3. The molybdenum tetrahydride species facilitates CO2 insertion into a metal hydride to produce a formate complex, (Triphos)Mo(H)(κ2-CHO2)(PPh3), with an observed rate constant of [2.9(2)] × 10–4 s–1 (25 °C), which is independent of CO2 pressure. Selective formation of acrylate and propionate carbon dioxide–ethylene coupling products, (Triphos)Mo(H)(κ2-C3H3O2)(PPh3) and (Triphos)Mo(H)(κ2-C3H5O2)(PPh3), was achieved by sequential addition of olefin and heterocumulene to (Triphos)Mo...

The Lewis acid tris(pentafluorophenyl)borane was found to rapidly promote ring-opening β-hydride elimination in a 1,1′-bis(diphenylphosphino)ferrocene (dppf) nickelalactone complex under ambient conditions. The thermodynamic product of nickelalactone ring-opening was characterized as (dppf)Ni(CH(CH3)CO2BArf3), the result of β-hydride elimination and subsequent 2,1-insertion from a transient nickel(II) acrylate hydride intermediate. Treatment of (dppf)Ni(CH(CH3)CO2BArf3) with a nitrogen-containing base afforded a diphosphine nickel(0) η2-acryl borate adduct. Formation of the diphosphine nickel(0) η2-acryl borate adduct completes a net conversion of nickelalactone to acrylate species, a significant obstacle to catalytic acrylate production from CO2 and ethylene. Displacement of the η2-acrylate fragment from the nickel center was accomplished by addition of ethylene to yield a free acrylate salt and (dppf)Ni(CH2═CH2).

The cobalt(III) dimethyl halide complexes cis,mer-(PMe3)3Co(CH3)2X (X = Cl, I) were found to undergo a degenerate cobalt-to-cobalt transfer of the methyl ligands during isotopic labeling experiment...

A metastable, polymorphic hexameric crystal structure of lithium pinacolone enolate (LiOPin) is reported along with three preparation methods. NMR-based structural characterization implies that the lithium pinacolate hexamer deaggregates to a tetramer in toluene but retains mainly the hexameric structure in nonaromatic hydrocarbon solvents such as cyclohexane. Moreover, the presence of a small amount of lithium aldolate (LiOA) dramatically influences the aggregation state of LiOPin by forming a mixed aggregate with a 3:1 ratio (LiOPin3·LiOA).

We report on the generation of a perfluoroalkyl Grignard reagent ((F)RMgX) by exchange reaction between a perfluoroalkyl iodide ((F)R-I) and a Grignard reagent (RMgX). (19)F NMR was applied to monitor the generation of n-C3F7MgCl. Additional NMR techniques, including (19)F COSY, NOESY, and pulsed gradient spin-echo (PGSE) diffusion NMR, were invoked to assign peaks observed in (19)F spectrum. Schlenk equilibrium was observed and was significantly influenced by solvent, diethyl ether, or THF.

A synthesis of representative monohydroxy derivatives of valinomycin (VLM) was achieved under mild conditions by direct hydroxylation at the side chains of the macrocyclic substrate using dioxiranes. Results demonstrate that the powerful methyl(trifluoromethyl)dioxirane 1b should be the reagent of choice to carry out these key transformations. Thus, a mixture of compounds derived from the direct dioxirane attack at the beta-(CH(3))(2)C-H alkyl chain of one Hyi residue (compound 3a) or of one Val moiety (compounds 3b and 3c) could be obtained. Following convenient mixture separation, each of the new oxyfunctionalized macrocycles became completely characterized.

article i nfo Keywords: Physiology Metabolism Dormancy Season Temperature Downregulation Q10 Diamondback terrapins experience broad fluctuations in temperature on both a daily and seasonal basis in their estuarine environment. We measured metabolic enzyme activity in terrapin muscle tissue to assess thermal dependence and the role of temperature in seasonal metabolic downregulation in this species. Activity of lactate dehydrogenase (LDH), pyruvate kinase (PK), citrate synthase (CS), and cytochrome c oxidase (CCO) was assayed at 10, 20, 30, and 40 °C for tissue collected during summer and winter. The Q10 for enzyme activity varied between 1.31 and 2.11 within the temperature range at which terrapins were active (20-40 °C). The Q10 for LDH, CS, and CCO varied between 1.39 and 1.76 and between 10 and 20 °C, but PK exhibited heightened thermal sensitivity within this lower temperature range, with a Q10 of 2.90 for summer- collected tissue and 5.55 for winter-collected tissue. There was no significant effect of season on activity of LDH or PK, but activity of CS and CCO was significantly lower in winter-collected tissue compared with summer-collected tissue. Results indicate that temperature effects contribute to seasonal metabolic downregulation and dormancy in terrapins, but other environmental factors (i.e. oxygen availability), as well as seasonal shifts in blood biochemistry and circulating hormones may also play an important role.

Biodiesel, fatty acid methyl esters derived from vegetable oils, is a well-established alternative to petroleum diesel. We have developed a rapid 1H diffusion-ordered nuclear magnetic resonance spectroscopy (DOSY NMR) method to resolve mixtures of mono-, di-, and triacyglycerols along with their methyl esters. Because of the differences in diffusion coefficients between the starting materials (triglycerides), intermediates (mono- and diglycerols), and products (methyl esters), we were able to accurately predict the formula weights of these species in solution. This technique was used to monitor transesterification reactions of virgin and waste vegetable oils. In addition to proving its utility to assess conversion of starting materials, we found that 1,3-diacylglycerol is the major intermediate formed during alkali-catalyzed biodiesel production.

Forest and grass riparian buffers are a common conservation practice to control nonpoint source pollution. In the lower midwestern United States, there is significant interest in incorporating a once common native riparian species, giant cane (Arundinaria gigantea) in riparian restoration designs. Thus, assessing the water quality benefits of giant cane buffers is warranted. Ground water nitrate and ammonium concentrations were measured at the field edge (0 m), and 1.5, 3.0, 6.0, 9.0, and 12.0 m from the field edge through giant cane and forest riparian buffers adjacent to agricultural fields along three streams in southern Illinois. Ground water nitrate and ammonium were not different between the giant cane and forest riparian buffers, nor were there significant reductions in these nutrients through the riparian zones when all three sites were considered. However, site-specific regressions of nutrient concentration vs. distance showed significant reductions (>80%) in nitrate through two forest a...

A chiral enolate aggregate 1 containing a lithium enolate and a chiral lithium amide was systematically investigated by various NMR techniques. (1)H and (13)C DOSY at 25 and -78 degrees C provide its solution structure, aggregation number, and formula weight. Multiple 2D (6)Li NMR techniques, such as (6)Li-(6)Li EXSY, (6)Li-(1)H HOESY, were utilized to investigate its stereochemical structure. The configuration of the enolate in complex 1 was confirmed by (6)Li-(1)H HOESY and trapping with TMS-Cl. A unique (6)Li-(1)H coupling through the Li-N-C-H network was observed. This scalar coupling was corroborated by (6)Li-(1)H HMQC, deuterium labeling experiments, and selective (1)H decoupling (6)Li NMR. The stereostructure of 1 provides a model for the origin of enantioselectivity of chiral lithium amide-induced enolate addition reactions.

A system consisting of a chiral lithium amide and n-BuLi in tol-d(8) solution was investigated with (1)H and (13)C INEPT DOSY, (6)Li and (15)N NMR, and other 2D NMR techniques. A mixed 2:1 trimeric complex was identified as the major species as the stoichiometry approached 1.5 equiv of n-BuLi to 1 equiv of amine compound. (1)H and (13)C INEPT DOSY spectra confirmed this lithium aggregate in the solution. The formula weight of the aggregate, correlated with diffusion coefficients of internal references, indicated the aggregation number of this complex. Plots of log D(rel) vs log FW are linear (r0.9900). (6)Li and (15)N NMR titration experiments also corroborated these results. These NMR experiments indicate that this mixed aggregate is the species that is responsible for asymmetric addition of n-BuLi to aldehydes.

Ethylphenidate is formed by metabolic transesterification of methylphenidate and ethanol. Study objectives were to (a) establish that ethylphenidate is formed in C57BL/6 (B6) mice; (b) compare the stimulatory effects of ethylphenidate and methylphenidate enantiomers; (c) determine methylphenidate and ethylphenidate plasma and brain distribution and (d) establish in-vitro effects of methylphenidate and ethylphenidate on monoamine transporter systems. Experimental results were that: (a) coadministration of ethanol with the separate methylphenidate isomers enantioselectively produced l-ethylphenidate; (b) d and dl-forms of methylphenidate and ethylphenidate produced dose-responsive increases in motor activity with stimulation being less for ethylphenidate; (c) plasma and whole-brain concentrations were greater for ethylphenidate than methylphenidate and (d) d and DL-methylphenidate and ethylphenidate exhibited comparably potent low inhibition of the dopamine transporter, whereas ethylphenidate was a less potent norepinephrine transporter inhibitor. These experiments establish the feasibility of the B6 mouse model for examining the interactive effects of ethanol and methylphenidate. As reported for humans, concurrent exposure of B6 mice to methylphenidate and ethanol more readily formed l-ethylphenidate than d-ethylphenidate, and the l-isomers of both methylphenidate and ethylphenidate were biologically inactive. The observed reduced stimulatory effect of d-ethylphenidate relative to d-methylphenidate appears not to be the result of brain dispositional factors, but rather may be related to its reduced inhibition of the norepinephrine transporter, perhaps altering the interaction of dopaminergic and noradrenergic neural systems.

We report the crystal structure of a substoichiometric, HMPA-trisolvated lithium pinacolone enolate tetramer (LiOPin)4·HMPA3 abbreviated as T3. In this tetramer one HMPA binds to lithium more strongly than the other two causing a reduction in spatial symmetry with corresponding loss of C3 symmetry. A variety of NMR experiments, including HMPA titration, diffusion coefficient-formula weight (D-FW) analysis, and other multinuclear one- and two-dimensional NMR techniques reveal that T3 is the major species in hydrocarbon solution when more than 0.6 equiv of HMPA is present. Due to a small amount of moisture from HMPA or air leaking into the solution, a minor complex was identified and confirmed by X-ray diffraction analysis as a mixed aggregate containing enolate, lithium hydroxide, and HMPA in a 4:2:4 ratio, [(LiOPin)4·(LiOH)2·HMPA4], that we refer to as pseudo-T4. A tetra-HMPA-solvated lithium cyclopentanone enolate tetramer was also prepared and characterized by X-ray diffraction, leading to the conclusion that steric effects dominate the formation and solvation of the pinacolone aggregates. An unusual mixed aggregate consisting of pinacolone enolate, lithium diisopropyl amide, lithium oxide, and HMPA in the ratio 5:1:1:2 is also described.

Reduction of the pincer nickel(ii) complex [(PNP)NiBr] with sodium amalgam (Na/Hg) forms the mercury-bridged dimer [{(PNP)Ni}2{μ-Hg}], which homolytically cleaves dihydrogen to form [(PNP)NiH]. Reversible CO2 insertion into the Ni-H bond is observed for [(PNP)NiH], forming the monodentate κ(1)O-formate complex [(PNP)NiOC(O)H].

Two forested watersheds (WS3 and WS9) in the central Appalachians were artificially acidified with ammonium sulfate fertilizer. WS9 was treated for 8 years, whereas WS3 has been treated for approximately 15 years. Soil leachate was collected from a depth of 46 cm (B horizon) in WS9 and below the A, B, and C horizons in WS3. Nitrate concentrations from WS3 increased for approximately 10–12 years (depending upon horizon) and then did not increase from 2000 through 2003 despite continued fertilizer treatments. Nitrate concentrations in WS9 soil water increased for the first 3 years of fertilization, and then declined for another 2 years. After that time, the concentrations remained relatively constant at approximately 15 µequiv.·L–1; this period of low nitrate concentrations included 2.3 years of fertilization followed by 8.2 years of no fertilization. Stream-water nitrate concentrations from both watersheds indicate they were in stage 2 of nitrogen saturation; however, the soil-water nitrate behavior observed within the setting of continued elevated nitrogen inputs is at odds with responses predicted in current nitrogen saturation theory. We believe that the cessation of nitrate increases in at least the B and C horizons were due primarily to abiotic retention, with recalcitrant forms of dissolved organic carbon providing the carbon needed to induce retention. These results show that nitrogen cycling in forest soil ecosystems is more complex than current nitrogen saturation theory suggests.

The influences of stream temperature, nitrate concentration, dissolved oxygen concentration, and substrata composition on potential denitrification rate (PDR) were investigated over one year in Big Creek, an agricultural watershed in southern Illinois. PDR ranged from 0 to 106 μg N g AFDM−1 hr−1 with higher rates in the early spring and late summer. The greatest PDR's were measured in April 2000 and April 2001, which both coincided with newly established periphyton communities. PDR did not correlate as expected with seasonally variable, ambient stream conditions such as temperature, dissolved oxygen or nitrate concentration; however, significant relationships did exist between PDR and dissolved oxygen within seasons. The coarse sediments from the headwater section of Big Creek had a significantly higher PDR (13.1 μg N g AFDM−1 hr−1) than the fine sediments (5.2 μg N g AFDM−1 hr−1) from the lower channelized reach, which may have been a function of lower C:N organic matter in the headwater reach. ...

Ethanol elevates methylphenidate (1) plasma concentrations and yields the metabolite ethylphenidate (2). The therapeutic implications are under investigation. The IC(50) for dopamine reuptake inhibition by (+)-2 was 27 nM compared to 367 nM for cocaine and 1730 nM for (-)-2. Binding selectivity for dopamine versus norepinephrine transporters was greater for (+)-2 than for cocaine. Intraperitoneal (+)-2 was approximately half as active as (+)-1 in stimulating mouse motor activity at 5 mg/kg, but (+)-2 was as active as (+)-1 at 10 mg/kg.

Although the large variations in nitrate export from forested watersheds have been at- tributed to a variety of natural and disturbance-related factors, baseflow nitrate concentrations in 49 mid-Appalachian forested watersheds were most strongly related to differences in bedrock geol- ogy. Within the mid-Appalachian region of Pennsylvania, Maryland and West Virginia, watersheds dominated by Pottsville and Allegheny sandstone (PVA), Catskill, Chemung, and Pocono shale and sandstone (CCP), and Mauch Chunk shale and Greenbrier limestone (MCG), respectively, exhibited significantly different low, intermediate, and high mean stream nitrate concentrations. Soil pH, soil percent N concentration (%N), soil C:N mass ratio, soil exchangeable Ca, watershed slope, and the occurrence of white ash (Fraxinus americana L.), sugar maple (Acer saccharum Marsh.), and eastern hemlock (Tsuga canadensis L.) were related significantly to bedrock geology type as well as stream nitrate levels. Other factors such as past land disturbances (fire and agriculture) and stand age (old- growth) typically were associated with only one bedrock geology type. However, within a bedrock geology type, past agriculture and the presence of old-growth forest may be important in explaining stream nitrate concentrations on an individual watershed basis. The basal area of black locust (Robinia pseudoacacia L.), a species that enhances soil nitrogen levels via nitrogen fixation, showed a moderate positive correlation with stream nitrate concentrations. Bedrock geology explained the most variation in winter (49%) and summer (32%) stream nitrate concentrations. Bedrock geology may have been a better predictor of stream nitrate concentrations than soil chemistry, because the geologic variation was better assessed at the regional scale of this study compared to soil chemistry, which varies at the micro-scale due to topographic, vegetation, microbial, and climatic influences. Results of this study suggest that bedrock geology is an important factor to consider when assessing forest nitrogen dynamics at a broad landscape scale.

Ground water contamination by excess nitrate leaching in row-crop fields is an important issue in intensive agricultural areas of the United States and abroad. Giant cane and forest riparian buffer zones were monitored to determine each cover type's ability to reduce ground water nitrate concentrations. Ground water was sampled at varying distances from the field edge to determine an effective width for maximum nitrate attenuation. Ground water samples were analyzed for nitrate concentrations as well as chloride concentrations, which were used as a conservative ion to assess dilution or concentration effects within the riparian zone. Significant nitrate reductions occurred in both the cane and the forest riparian buffer zones within the first 3.3 m, a relatively narrow width. In this first 3.3 m, the cane and forest buffer reduced ground water nitrate levels by 90 percent and 61 percent, respectively. Approximately 40 percent of the observed 99 percent nitrate reduction over the 10 m cane buffer could be attributed to dilution by upwelling ground water. Neither ground water dilution nor concentration was observed in the forest buffer. The ground water nitrate attenuation capabilities of the cane and forest riparian zones were not statistically different. During the spring, both plant assimilation and denitrification were probably important nitrate loss mechanisms, while in the summer nitrate was more likely lost via denitrification since the water table dropped below the rooting zone.

Two methods used for a puff-by-puff determination of the pH of water-extractables of cigarette smoke were compared. Particulate and whole smoke data for Kentucky Reference Cigarettes 1R3F, 1R4F, and 1R5F and for a commercial cigarette brand were collected. Mainstream particulate for each puff was collected separately on glass-fiber filter pads. The pads were extracted with deionized water (particulate method) or deionized water purged with exhaust from the smoking machine (whole smoke method) and the pH was measured. Particulate-method pH was inversely related to the amount of particulate collected, allowing for true comparisons between individual puffs from the same cigarette and between cigarette types. The whole smoke method lacked the sensitivity to distinguish between samples and is of little use as a comparative tool, probably because of the large contribution of carbon dioxide.