Synthesis,Structure, and DFT Analysis of the THF Solvate of 2-Picolyllithium: A 2-Picolyllithium Solvate with Significant Carbanionic Character

Previous studies of different solvates of 2-methylpyridyllithium (2-picolyllithium) have uncovered electronic structures corresponding to aza-allyl and enamido resonance forms of the metallated pyridine-based compounds. Here, we report the synthesis and characterization of [2-CH₂Li(THF)₂C₅H₄N], a new THF solvate. X-ray crystallographic studies reveal a dimeric arrangement featuring a non-planar eight-membered [NCCLi]₂ ring, in which the primary cation-anion interaction is between the central Li atom and the C atom of the deprotonated methyl group [length, 2.285(2) Å], suggesting a new carbanionic resonance structure for this 2-picolyllithium series. The significant carbanionic character of [2-CH₂Li(THF)₂C₅H₄N] was confirmed by gas-phase DFT calculations [B3LYP/6-311+G(d)] with the calculated electron density interrogated by means of quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses. For comparison these computational analyses were also performed on the literature structures of [2-CH₂Li(2-Picoline)C₅H₄N] and [2-CH₂Li(PMDETA)C₅H₄N]. In a reactivity study, [2-CH₂Li(THF)₂C₅H₄N] was found to undergo nucleophilic addition to pyridine to generate dipyridylmethane in a good yield.     

Density conservation for a coagulation equation

A Theorem is presented which proves that solutions to the coagulation equation are density conserving whenever certain growth assumptions are made on the coagulation kernel.     

On the greatest prime factor of integers of the form ab + 1

Let N be a positive integer and let A and B be dense subsets of {1,...,N }. The purpose of this paper is to establish a good lower bound for the greatest prime factor of ab + 1as a and b run over the elements of A and B respectively.     

HPLC separations of meropenem and selected pharmaceuticals using a polar endcapped octadecylsilane narrow bore column

Summary Stability indicating high performance liquid chromatography methods have been developed for the assay of meropenem in combination with either dopamine (A), aminophylline (B), metoclopramide (C) or ranitidine (D) in intravenous fluid mixtures. Separations B, C and D were performed on a polar endcapped ODS column (150×2 mm) with aqueous, pH 3.0—acetonitrile (89∶11, 88∶12, and 92∶8) eluent and detection at 270, 290, 317 nm respectively. Meropenem was linear over the concentration ranges 126.88–507.50, 131.25–525, and 131.25–525 gmg mL⁻¹. Aminophylline, metoclopramide and ranitidine were linear over the concentration ranges 13–52, 37.5–150, and 25–100 μg mL⁻¹. Separation A was performed on a conventional ODS column (150×2.1 mm) with aqueous, pH 3.0—acetonitrile (85∶15) eluent and detection at 280 nm. Meropenem and dopamine were linear in the 61.25–245 and 10–40 μg mL⁻¹ ranges, respectively. Accuracy and precision for all methods were 0.20–3.30% and 0.10–1.58%, respectively. Accelerated stability studies have been carried out on each drug by exposure to acid, base, H₂O₂, and heat for different time periods.     

Synthesis and biological evaluation of anthranilamide-based non-peptide mimetics of ω-conotoxin GVIA

Non-peptide mimetics based on an anthranilamide ‘scaffold’ possessing fragments that mimic Lys2, Tyr13 and Arg17 in ω-conotoxin GVIA have been prepared. Compounds were assayed for binding to the voltage-gated calcium channels Ca_v2.2 (‘N-type’) and Ca_v2.1 (‘P/Q-type’) in rat brain. The primary synthetic target, 2-(6-amino-hexanoylamino)-5-(3-guanidino-propoxy)-N-[4-(4-hydroxyphenoxy)-phenyl]-benzamide (2a), exhibited low μM binding to Ca_v2.2 and was more than 30-fold selective for Ca_v2.2 over Ca_v2.1.     

A collaborative hit-to-lead investigation leveraging medicinal chemistry expertise with high throughput library design, synthesis and purification capabilities

High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed.     

In situ auger electron spectroscopy study of atomic layer deposition: growth initiation and interface formation reactions during ruthenium ALD on Si-H, SiO2, and HfO2 surfaces

Growth initiation and film nucleation in atomic layer deposition (ALD) is important for controlling interface composition and achieving atomic-scale films with well-defined composition. Ruthenium ALD is studied here using ruthenocene and oxygen as reactants, and growth initiation and nucleation are characterized on several different growth surfaces, including SiO2, HfO2, and hydrogen terminated silicon, using on-line Auger electron spectroscopy and ex-situ X-ray photoelectron spectroscopy. The time needed to reach the full growth rate (typically approximately 1 A per deposition cycle) is found to increase as the surface energy of the starting surface (determined from contact angle measurements) decreased. Growth starts more readily on HfO2 than on SiO2 or Si-H surfaces, and Auger analysis indicates distinct differences in surface reactions on the various surfaces during film nucleation. Specifically, surface oxygen is consumed during ruthenocene exposure, so the nucleation rate will depend on the availability of oxygen and the energetics of surface oxygen bonding on the starting substrate surface.