Tandem (quadrupole-time-of-flight) electrospray mass spectrometry of oligo(vinyl acetates) with isopropylol or (1-hydroxyethyl)-2-oxyisopropanyl end groups

Poly(vinyl acetates) with either isopropylol or (1-hydroxyethyl)-2-oxyisopropanyl end groups were analysed by tandem mass spectrometry using a quadrupole-time-of-flight (Q-TOF) instrument. Random scission along the polymer backbone was not observed. Instead the initial scissions were derived from the cleavage of end-group species. The resultant macrocations were subject to further elimination reactions that eventually produced polyene macrocations. A smaller fraction of the initial macrocations also reacted by loss of ketene and this reaction produced macrocations containing vinyl alcohol units.     

Continuous flow in open microfluidics using controlled evaporation

This paper presents a method for programming the flow rate of liquids inside open microfluidic networks (MFNs). A MFN comprises a number of independent flow paths, each of which starts with an open filling port, has a sealed microchannel in which assays can be performed, and an open capillary pump (CP). The MFN is placed over Peltier elements and its flow paths initially fill owing to capillary forces when liquids are added to the filling ports. A cooling Peltier element underneath the filling ports dynamically prevents evaporation in all filling ports using the ambient temperature and relative humidity as inputs. Another Peltier element underneath the CPs heats the pumps thereby inducing evaporation in the CPs and setting the flow rate in the microchannels. This method achieves flow rates in the microchannels ranging from approximately 1.2 nL s(-1) to approximately 30 pL s(-1), and is able to keep 90% of a 0.6 microL solution placed in an open filling port for 60 min. This simple and efficient method should be applicable to numerous assays or chemical reactions that require small and precise flow of liquids and reagents inside microfluidics.     

The use of 1H NMR microscopy to study proton-exchange membrane fuel cells.

To understand proton-exchange membrane fuel cells (PEMFCs) better, researchers have used several techniques to visualize their internal operation. This Concept outlines the advantages of using 1H NMR microscopy, that is, magnetic resonance imaging, to monitor the distribution of water in a working PEMFC. We describe what a PEMFC is, how it operates, and why monitoring water distribution in a fuel cell is important. We will focus on our experience in constructing PEMFCs, and demonstrate how 1H NMR microscopy is used to observe the water distribution throughout an operating hydrogen PEMFC. Research in this area is briefly reviewed, followed by some comments regarding challenges and anticipated future developments.     

Computation of the physio-chemical properties and data mining of large molecular collections

Very large data sets of molecules screened against a broad range of targets have become available due to the advent of combinatorial chemistry. This information has led to the realization that ADME (absorption, distribution, metabolism, and excretion) and toxicity issues are important to consider prior to library synthesis. Furthermore, these large data sets provide a unique and important source of information regarding what types of molecular shapes may interact with specific receptor or target classes. Thus, the requirement for rapid and accurate data mining tools became paramount. To address these issues Pharmacopeia, Inc. formed a computational research group, The Center for Informatics and Drug Discovery (CIDD).* In this review we cover the work done by this group to address both in silico ADME modeling and data mining issues faced by Pharmacopeia because of the availability of a large and diverse collection (over 6 million discrete compounds) of drug-like molecules. In particular, in the data mining arena we discuss rapid docking tools and how we employ them, and we describe a novel data mining tool based on a ID representation of a molecule followed by a molecular sequence alignment step. For the ADME area we discuss the development and application of absorption, blood-brain barrier (BBB) and solubility models. Finally, we summarize the impact the tools and approaches might have on the drug discovery process.     

Simultaneous multichannel mass-specific detection for high-performance liquid chromatography using an array detector sector-field mass spectrometer

The use of a separation step, such as liquid chromatography, prior to inductively coupled plasma mass spectrometry (ICP–MS) has become a common tool for highly selective and sensitive analyses. This type of coupling has several benefits including the ability to perform speciation analysis or to remove isobaric interferences. Several limitations of conventional instruments result from the necessity to scan or pulse the mass spectrometer to obtain a complete mass spectrum. When the instrument is operated in such a non-continuous manner, duty cycle is reduced, resulting in poorer absolute limits of detection. Additionally, with scanning instruments, spectral skew can be introduced into the measurement, limiting quantitation accuracy. To address these shortcomings, a high-performance liquid chromatograph has been coupled to an ICP–MS capable of continuous sample introduction and simultaneous multimass detection. These features have been realized with a novel detector array, the focal plane camera. Instrument performance has been tested for both speciation analysis and for the elimination of isobaric interferences. Absolute limits of detection in the sub picogram to tens of picograms regime are obtainable, while the added mass dimension introduced by simultaneous detection dramatically increases chromatographic peak capacity.     

Enantioselective epoxidation of alkenes catalyzed by 2-fluoro-N-carbethoxytropinone and related tropinone derivatives

Several alpha-substituted N-carbethoxytropinones have been evaluated as catalysts for asymmetric epoxidation of alkenes with Oxone, via a dioxirane intermediate. alpha-Fluoro-N-carbethoxytropinone (2) has been studied in detail and is an efficient catalyst which does not suffer from Baeyer-Villiger decomposition and can be used in relatively low loadings. This ketone was prepared in enantiomerically pure form using chiral base desymmetrization of N-carbethoxytropinone. Asymmetric epoxidation catalyzed by 2 affords epoxides with up to 83% ee. Among other derivatives tested, the alpha-acetoxy derivative 7 affords the highest enantioselectivities.     

Oxygen isotope corrections for online delta(34)S analysis

Elemental analyzers have been successfully coupled to stable-isotope-ratio mass spectrometers for online measurements of the delta(34)S isotopic composition of plants, animals and soils. We found that the online technology for automated delta(34)S isotopic determinations did not yield reproducible oxygen isotopic compositions in the SO(2) produced, and as a result calculated delta(34)S values were often 1-3 per thousand too high versus their correct values, particularly for plant and animal samples with high C/S ratio. Here we provide empirical and analytical methods for correcting the S isotope values for oxygen isotope variations, and further detail a new SO(2)-SiO(2) buffering method that minimizes detrimental oxygen isotope variations in SO(2).     

Deprotonation-electrophile trapping of terminal epoxides

Organolithium-induced deprotonation of terminal epoxides in the presence of appropriate diamine ligands allows trapping with a range of electrophiles, yielding functionalised di- and tri-substituted epoxides in good yields and with control of stereochemistry at the epoxide.     

Molecular Beam Mass Spectrometry System for Characterization of Thermal Plasma Chemical Vapor Deposition

A molecular beam mass spectrometry system for in situ measurement of the concentration of gas phase species including radicals impinging on a substrate during thermal plasma chemical vapor deposition (TPCVD) has been designed and constructed. Dynamically controlled substrate temperature was achieved using a variable thermal contact resistance method via a backside flow of an argon/helium mixture. A high quality molecular beam with beamtobackground signal greater than 20 was obtained under film growth conditions by sampling through a small nozzle (75 m) in the center of the substrate. Mass discrimination effects were accounted for in order to quantify the species measurements. We demonstrate that this system has a minimum detection limit of under 100 ppb. Quantitative measurements of hydrocarbon species (H, H₂, C, CH₃, CH₄, C₂H₂, C₂H₄) using Ar/H₂/CH₄ mixtures and silicon species (Si, SiH, SiH₂, SiCl, SiCl₂, Cl, HCl) using Ar/H₂/SiCl₄ mixtures were obtained under thermal plasma chemical vapor deposition conditions.     

Electron affinity of the guanine-cytosine base pair and structural perturbations upon anion formation

The adiabatic electron affinity (AEA) for the Watson-Crick guanine-cytosine (GC) DNA base pair is predicted using a range of density functional methods with double- and triple-zeta plus polarization plus diffuse (DZP++ and TZ2P++) basis sets in an effort to bracket the true electron affinity. The methods used have been calibrated against a comprehensive tabulation of experimental electron affinities (Chem.Rev. 2002, 102, 231). Optimized structures for GC and the GC anion are compared to the neutral and anionic forms of the individual bases as well as Rich's 1976 X-ray structure for sodium guanylyl-3',5'-cytidine nonahydrate, GpC.9H(2)O. Structural distortions and natural population (NPA) charge distributions of the GC anion indicate that the unpaired electron is localized primarily on the cytosine moiety. Unlike treatments using second-order perturbation theory (MP2), density functional theory consistently predicts a substantial positive adiabatic electron affinity for the GC pair (e.g., TZ2P++/B3LYP: +0.48 eV). The stabilization of C(-) via three hydrogen bonds to guanine is sufficient to facilitate adiabatic binding of an electron to GC and is also consistent with the positive experimental electron affinities obtained by photoelectron spectroscopy of cytosine anions incrementally microsolvated with water molecules. The pairing (dissociation) energy for GC(-) (35.6 kcal/mol) is determined with inclusion of electron correlation and shows the anion to have greater thermodynamic stability; the pairing energy for neutral GC (TZ2P++/B3LYP 23.9 kcal/mol) compares favorably to previous MP2/6-31G (23.4 kcal/mol) results and a debated experiment (21.0 kcal/mol).