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Mechanisms of Nickel-Catalyzed Coupling Reactions and Applications in Alkene Functionalization

ConspectusNickel complexes exhibit distinct properties from other group 10 metals, including a small nuclear radius, high paring energy, low electronegativity, and low redox potentials. These properties enable Ni catalysts to accommodate and stabilize paramagnetic intermediates, access radical pathways, and undergo slow beta-H elimination. Our research program investigates how each of these fundamental attributes impact the catalytic properties of Ni, in particular in the context of alkene functionalization.Alkenes are versatile functional groups, but stereoselective carbofunctionalization reactions of alkenes have been underdeveloped. This challenge may derive from the difficulty of controlling selectivity via traditional two-electron migratory insertion pathways. Ni catalysts could lead to different stereodetermining steps via radical mechanisms, allowing access to molecular scaffolds that are otherwise difficult to prepare. For example, an asymmetric alkene diarylation reaction developed by our group relies upon the radical properties of Ni(III) intermediates to control the enantioselectivity and give access to a library of chiral alpha,alpha,beta-triarylethane molecules with biological activity.Mechanistic studies on a two-component reductive 1,2-difunctionalization reaction have shed light on the origin of the cross-electrophile selectivity, as C sp2 and C sp3 electrophiles are independently activated at Ni(I) via two-electron and radical pathways, respectively. Catalyst reduction has been identified to be the turnover-limiting step in this system. A closer investigation of the radical formation step using a (Xantphos)Ni(I)Ar model complex reveals that Ni(I) initiates radical formation via a concerted halogen-abstraction pathway.The low redox potentials of Ni have allowed us to develop a reductive, trans-selective diene cyclization, wherein a classic two-electron mechanism operates on a Ni(I)/Ni(III) platform, accounting for the chemo- and stereoselectivity. This reaction has found applications in the efficient synthesis of pharmaceutically relevant molecules, such as 3,4-dimethylgababutin.The tendency of Ni to undergo one-electron redox processes prompted us to explore dinuclear Ni-mediated bond formations. These studies provide insight into Ni-Ni bonding and how two metal centers react cooperatively to promote C-C, C-X, and N-N bond forming reductive elimination.Finally, isolation of beta-agostic Ni and Pd complexes has allowed for X-ray and neutron diffraction characterization of these highly reactive molecules. The bonding parameters serve as unambiguous evidence for beta-agostic interactions and help rationalize the slower beta-H elimination at Ni relative to Pd. Overall, our research has elucidated the fundamental properties of Ni complexes in several contexts. Greater mechanistic understanding facilitates catalyst design and helps rationalize the reactivity and selectivity in Ni-catalyzed alkene functionalization reactions.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF A PYRIDO<3',4':5,4>PYRROLO<1,2-c>–<1,4>BENZODIAZEPINE-3,10-DIONE, A NEW BENZODIAZEPINE-&beta-CARBOLINE TYPE HYBRID MOLECULE

Diethyl 2,3-dihydro-6-azaindoline-2,5-dicarboxylate 4b was synthesized and used as starting material in the preparation of a novel benzodiazepine-beta-carboline type hybrid molecule (3aR,S)-ethyl 3,10-dioxo-2,3,3a,4-tetrahydro-10H-pyrido<3',4':5,4>pyrrolo<1,2-c><1,4>-benzodiazepine-6-carboxylate 5b.The benzodiazepine receptor binding affinities of this compound and its precursors were found to be very modest in vitro.These results confirm our previously proposed model of the configuration of the benzodiazepine and beta-carboline binding sites on the receptor as represented by the configuration of these two moieties in the high affinity hybrid 3.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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A second order group contribution method for the prediction of critical temperatures and enthalpies of vaporization of organic compounds

A new method based on group contribution additivity, and using Benson’s second order groups, is proposed for the prediction of critical temperatures and enthalpies of vaporization of covalent compounds. Contributions for hydrocarbons and hydrocarbon derivatives containing oxygen, nitrogen, chlorine, bromine and/or sulphur, are given. Results are compared to predictions made using the most common existing first or second order group contribution methods. The overall precision for Tc predictions of 381 compounds is 5.8 K, compared to 23.6 K with the method of Joback and 9.2 K with the method of Constantinou. The precision for predicted DeltaHvap of 319 compounds, at 298 K and at the normal boiling point, is improved by a factor 2 when comparing to the results of the method of Svoboda. Furthermore, one single group decomposition may now be used for the computation of gas phase properties, Tc, and DeltaHvap at any temperature lower than T c, leading to liquid phase thermochemical functions with better precision and simplicity.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Calibration of the mobility scale in ion mobility spectrometry: The use of 2,4-lutidine as a chemical standard, the two-standard calibration method and the incorrect use of drift tube temperature for calibration

Ion mobility spectrometry (IMS) is an analytical technique that separates ions in the gas phase under the influence of an electric field according to their size to charge ratio. We used electrospray ionization IMS-quadrupole mass spectrometry to study the mobility shifts of 2,4-lutidine with temperature or the introduction of several contaminants in the drift gas. We found the reduced mobility (K0) of 2,4-lutidine to decrease up to 24% when contaminants were introduced into the drift gas. We also show the significant variation of 2,4-lutidine’s K0 with the drift tube temperature, 8.5% from 100 to 322 C. These changes in 2,4-lutidine’s mobility were due to variations in clustering by changes in temperature or contaminant concentration. This dependence of 2,4-lutidine’s K0 with temperature and contamination in the drift gas makes this chemical standard unsuitable to calibrate the mobility scale. Despite these findings, 2,4-lutidine is still used for this purpose. The shortcomings of the IMS two-standard calibration and the incorrect use of the drift tube temperature for calibration are also discussed. We suggest that accurate reduced mobilities must be determined for small ions only in a highly purified drift gas using calibrants with a well determined K0 such as di tert-butyl pyridine at high temperatures, where clustering is low, and the drift gas temperature is measured instead of the drift tube temperature.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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In homogeneous catalysis, the catalyst is in the same phase as the reactant. The number of collisions between reactants and catalyst is at a maximum.In a patent, 108-47-4, name is 2,4-Dimethylpyridine, introducing its new discovery. category: chiral-nitrogen-ligands

Simple derivatization method for sensitive determination of fatty acids with fluorescence detection by high-performance liquid chromatography using 9-(2-hydroxyethyl)-carbazole as derivatization reagent

A simple and sensitive method for the determination of short and long-chain fatty acids using high-performance liquid chromatography with fluorimetric detection has been developed. The fatty acids were derivatized to their corresponding esters with 9-(2-hydroxyethyl)-carbazole (HEC) in acetonitrile at 60C with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride as a coupling agent in the presence of 4-dimethylaminopyridine (DMAP). A mixture of esters of C1-C20 fatty acids was completely separated within 38 min in conjunction with a gradient elution on a reversed-phase C18 column. The maximum fluorescence emission for the derivatized fatty acids is at 365 nm (lambdaex 335 nm). Studies on derivatization conditions indicate that fatty acids react proceeded rapidly and smoothly with HEC in the presence of EDC and DMAP in acetonitrile to give the corresponding sensitively fluorescent derivatives. The application of this method to the analysis of long chain fatty acids in plasma is also investigated. The LC separation shows good selectivity and reproducibility for fatty acids derivatives. The R.S.D. (n = 6) for each fatty acid derivative are <4%. The detection limits are at 45-68 fmol levels for C14-C20 fatty acids and even lower levels for category: chiral-nitrogen-ligands

Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Pyridines in cigarette smoke inhibit hamster oviductal functioning in picomolar doses

Past studies showed that chemicals in cigarette smoke inhibit oviductal functioning in vivo and in vitro. The purposes of this study were to identify individual toxicants in cigarette smoke solutions that inhibit various aspects of oviductal functioning and to determine their effective doses using in vitro bioassays. Solid phase extraction and gas chromatography-mass spectrometry (GC-MS) were used to identify individual chemicals in mainstream (MS) and sidestream (SS) cigarette smoke solutions. Pyridines, which were the most abundant class of compounds identified, were purchased, assayed for purity, and tested in dose-response studies on hamster oviducts. The lowest observable adverse effect level was determined for each pyridine derivative using the oocyte pick-up rate, ciliary beat frequency, and infundibular muscle contraction assays. 2-Methylpyridine, 4-methylpyridine, 2-ethylpyridine, 3-ethylpyridine, and 4-vinylpyridine were inhibitory at picomolar concentrations in all assays. This work shows picomolar doses of pyridines with single methyl or ethyl substitutions significantly inhibit oviductal functioning raising questions regarding the safety of these compounds.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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A study of adduct formation of heterocyclic nitrogen bases with nickel(II) chelate of di(6-chloro-2-methylphenyl)carbazone.

The study of the adduct formation of Ni(II) di(6-chloro,2-methylphenyl)carbazonate has been undertaken by synthesising and characterizing it by magnetic susceptibility, UV-VIS, IR and 1H-NMR spectral measurements. The distorted square planar Ni(II) chelate forms adducts with heterocyclic nitrogen bases; spectrophotometric method has been employed for the study of the adduct formation in a monophase chloroform. Both bidentate and unsaturated monodentate heteronuclear nitrogen bases form hexacoordinated adducts with 1:1 and 1:2 stoichiometry, respectively (metalchelate:base). However, the saturated nitrogen bases form pentacoordinated adducts with 1:1 stoichiometry. The results are discussed in terms of basicity and steric factors of the bases.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Analysis of hazardous chemicals by “stand alone” drift tube ion mobility spectrometry: A review

Ion mobility spectrometry (IMS) is a widely used technique based on gas phase ion separation under an electric field by differences in ion mobilities. In the last decade, IMS techniques have received increased attention due to their high operational speed and sensitivity. Currently, there are different IMS devices focused on solving different analytical performances, mainly based on linear drift tube (DT IMS), traveling wave, and field asymmetric waveform ion mobility spectrometers. In this review we summarize the main applications of DT-IMS devices for the determination of semi-volatile hazardous chemicals such as: illegal drugs, pesticides, explosives, chemical warfare agents, and others, in different matrices, in order to provide a detailed view of the analytical features of the technique.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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REACTIONS OF PERCHLORO-2-CYCLOPENTEN-1-ONE AND PERCHLORO-4-CYCLPENTENE-1,3-DIONE WITH PYRIDINE AND QUINOLINE DERIVATIVES

By the reaction of perchloro-2-cyclopenten-1-one with pyridine and quinoline derivatives the corresponding onium salts of 2,4,4,5,5-pentachloro-3-hydroxy-2-cyclopentenone were obtained.The analogous reactions of perchloro-4-cyclopentene-1,3-dione lead either to onium salts of 2,2,5-trichloro-4-hydroxy-4-cyclopentene-1,3-dione or to betaines.The effect of the nature of the solvent and the structure of the amine on the reaction path was examined.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Design, synthesis, and crystal structures of 6-alkylidene-2?- substituted penicillanic acid sulfones as potent inhibitors of acinetobacter baumannii OXA-24 carbapenemase

Class D beta-lactamases represent a growing and diverse class of penicillin-inactivating enzymes that are usually resistant to commercial beta-lactamase inhibitors. As many such enzymes are found in multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa, novel beta-lactamase inhibitors are urgently needed. Five unique 6-alkylidene-2?-substituted penicillanic acid sulfones (1-5) were synthesized and tested against OXA-24, a clinically important beta-lactamase that inactivates carbapenems and is found in A. baumannii. Based upon the roles Tyr112 and Met223 play in the OXA-24 beta-lactamase, we also engineered two variants (Tyr112Ala and Tyr112Ala,Met223Ala) to test the hypothesis that the hydrophobic tunnel formed by these residues influences inhibitor recognition. IC50 values against OXA-24 and two OXA-24 beta-lactamase variants ranged from 10 ¡À 1 (4 vs WT) to 338 ¡À 20 nM (5 vs Tyr112Ala, Met223Ala). Compound 4 possessed the lowest Ki (500 ¡À 80 nM vs WT), and 1 possessed the highest inactivation efficiency (kinact/ Ki = 0.21 ¡À 0.02 muM-1 s-1). Electrospray ionization mass spectrometry revealed a single covalent adduct, suggesting the formation of an acyl-enzyme intermediate. X-ray structures of OXA-24 complexed to four inhibitors (2.0-2.6 A) reveal the formation of stable bicyclic aromatic intermediates with their carbonyl oxygen in the oxyanion hole. These data provide the first structural evidence that 6-alkylidene-2?-substituted penicillin sulfones are effective mechanism-based inactivators of class D beta-lactamases. Their unique chemistry makes them developmental candidates. Mechanisms for class D hydrolysis and inhibition are discussed, and a pathway for the evolution of the BlaR1 sensor of Staphylococcus aureus to the class D beta-lactamases is proposed.

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Reference£º
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis¡ªI. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis