A New Series of Proton/Charge Transfer Molecules: Synthesis and Spectral Studies of 2-(5-Aryl-1-carbomethoxy-1H-pyrazol-3-yl)phenols

Abstract. The carbomethoxyhydrazone of 2'-hydroxyacetophenone was trilithiated with excess lithium diisopropylamide and C-acylated with a variety of benzoate esters followed by acid cyclization of the intermediates to 2-(5-aryl-l-car-bomethoxy-lHpyrazol-3-yl)phenols [3-(2-hydroxyphen-yl)-lH-pyrazoles]. The products were characterized by Fourier transform-IR, ^lH NMR, ¹³C NMR, UV-visible absorption and fluorescence. All the derivatives in n -heptane have an absorption maximum at ˜304 nm and an extremely weak (φ_r= 10 ⁴) fluorescence with maxima in the range of 335–460 nm. The broad range of fluorescence maxima and fluorescence quantum yields is attributed to varying contributions of charge transfer that are dependent on both the identity of the substituent and solvent polarity. A phenomenally large Stokes-shifted fluorescence maximum at 620 nm was observed for 2-(l-car-bomethoxy-5-[4-dimethylaminophenyl]-lff-pyrazol-3-y1)phenol in n-heptane and attributed to excited-state intramolecular proton transfer. As a result, competitive excited-state proton/charge transfer properties have been observed in the pyrazoles studied, of which the spectral properties can be fine tuned by substituent as well as solvent effects.     

On powers associated with Sierpiński numbers, Riesel numbers and Polignac's conjecture

We address conjectures of P. Erd?s and conjectures of Y.-G. Chen concerning the numbers in the title. We obtain a variety of related results, including a new smallest positive integer that is simultaneously a Sierpiński number and a Riesel number and a proof that for every positive integer r, there is an integer k such that the numbers k,k²,k³,…,kr are simultaneously Sierpiński numbers.     

Photodesorption of alkali anions from alkali-halide cluster anions

Using photoelectron spectroscopy, we have observed alkali anion photodesorption from alkali-halide cluster anions that contain two weakly bound electrons. In the alkali iodides, we have found this type of desorption in almost every (MI)(n)M- cluster we have studied (M=Na, K, Cs; n<9), although it depends on the probe laser frequency and cluster temperature. Using pump-probe techniques, we have shown that the process occurs on a picosecond time scale by way of an electronic excitation of the cluster's spin-paired electrons.     

A rapid and precise assay for peroxide as 'active oxygen' in products, by flow injection analysis in a high pressure system with spectrophotometric detection

A simple, rapid and automated assay for ‘active oxygen’ originating from hydrogen peroxide, or other organic peroxides, in products is presented employing flow injection (FI) analysis. The product is dispersed and peroxide dissolved in a solvent of 5% (v/v) acetic acid, which constitutes the carrier stream. Ammonium molybdate can be added to this carrier stream to increase sensitivity as required. The sample solution is injected into the acid carrier stream, which is then merged with iodide ion in situ in a two-stream manifold. The ‘active oxygen’ in the product oxidises acidified iodide to iodine, which is detected spectrophotometrically at 350 nm. The closed conditions prevent interference from atmospheric oxygen and the short reaction time minimises the potential for interference from side reactions. Standard HPLC equipment is used throughout, employing a back-pressure to improve precision (high pressure flow injection). Conditions have been investigated using screening multivariate experimental design (two-level quarter fractional factorial design incorporating centre points) to identify and optimise the critical variables. The method has been fully validated (with sample solution R.S.D.s typically < 0.5%, LOQs of 0.04 or 0.006 μg ml⁻¹ as ‘active oxygen’ for acid or acid/molybdate carriers respectively) and is quicker and simpler than the currently employed manual titration approach. It should be applicable to a range of ‘active oxygen’ products.     

Development of a contact call in black-capped chickadees (Poecile atricapillus) hand-reared in different acoustic environments

The tseet contact call, common to black-capped (Poecile atricapillus) and mountain chickadees (P. gambeli), is the most frequently produced vocalization of each species. Previous work has characterized the tseet call of black-capped and mountain chickadees from different geographic locations in terms of nine acoustic features. In the current study, using similar methods, the tseet call of black-capped chickadees that were hand reared with either conspecifics, heterospecifics (mountain chickadees), or in isolation from adult chickadees are described. Analysis of call features examined which acoustic features were most affected by rearing environment, and revealed that starting frequency and the slope of the descending portion of the tseet call differed between black-capped chickadees reared with either conspecific or heterospecific adults. Birds reared in isolation from adults differed from the other hand-reared groups on almost every acoustic feature. Chickadee tseet calls are more individualized when they are reared with adult conspecifics or heterospecifics compared to chickadees that are reared in isolation from adults. The current results suggest a role of learning in this commonly used contact call.     

Mixed-metal Pt monolayer electrocatalysts with improved CO tolerance

Using a combination of periodic, self-consistent, density functional theory (DFT) calculations and CO-stripping voltammetry experiments, we have designed a new class of Pt-M bimetallic monolayer catalysts supported on a non-Pt metal, which exhibit improved stability against CO poisoning and might be suitable for proton-exchange membrane fuel cell anodes. These surfaces help in reducing the overpotential associated with anodic CO oxidation and minimize the amount of Pt used, thereby reducing materials cost. DFT calculations predict highly repulsive interactions between adsorbed CO molecules on these surfaces, leading to weaker binding and lower coverage of CO than on pure Pt, which in turn facilitates oxidative removal of CO from these catalytic surfaces.     

An Aggregation‐Induced‐Emission Platform for Direct Visualization of Interfacial Dynamic Self‐Assembly

An in‐depth understanding of dynamic interfacial self‐assembly processes is essential for a wide range of topics in theoretical physics, materials design, and biomedical research. However, direct monitoring of such processes is hampered by the poor imaging contrast of a thin interfacial layer. We report in situ imaging technology capable of selectively highlighting self‐assembly at the phase boundary in real time by employing the unique photophysical properties of aggregation‐induced emission. Its application to the study of breath‐figure formation, an immensely useful yet poorly understood phenomenon, provided a mechanistic model supported by direct visualization of all main steps and fully corroborated by simulation and theoretical analysis. This platform is expected to advance the understanding of the dynamic phase‐transition phenomena, offer insights into interfacial biological processes, and guide development of novel self‐assembly technologies.     

Cohort Analysis Technique for Long-Term Manpower Planning: the Case of a Hong Kong Tertiary Institution

This paper considers the problem of long-term manpower planning on the number of teaching staff for the case of a tertiary institution—the City Polytechnic of Hong Kong (CPHK). Due to the high turnover experienced in recent years, it is found necessary to study the wastage pattern of staff, defined as the number of new appointees who have left CPHK employment, rather than simply addressing just the issue of strength (namely number in post). A cohort analysis technique is therefore applied to characterize statistically the wastage rate as related to the length of service of individual cohorts of staff, being groups of newcomers joining CPHK in the same periods of time. This results in a log-normal model, showing a significant cohort specific effect on the wastage behaviour. Extending this cohort analysis technique, together with double exponential smoothing forecasts, to future retention rates (1 — cumulative wastage rates), a long-term planning model is constructed to study the relation between expected yearly recruitment levels and the target manpower requirements for the future five-year planning horizon. While the idea and model developed here are generally applicable, the present computational results provide valuable decision supports for an actual case study, for CPHK in particular.     

Quantitation of a PEGylated protein in monkey serum by UHPLC-HRMS using a surrogate disulfide-containing peptide: A new approach to bioanalysis and in vivo stability evaluation of disulfide-rich protein therapeutics

To quantify a therapeutic PEGylated protein in monkey serum as well as to monitor its potential in vivo instability and methionine oxidation, a novel ultra high performance liquid chromatography-high resolution mass spectrometric (UHPLC-HRMS) assay was developed using a surrogate disulfide-containing peptide, DCP(SS), and a confirmatory peptide, CP, a disulfide-free peptide. DCP(SS) was obtained by eliminating the step of reduction/alkylation before trypsin digestion. It contains an intact disulfide linkage between two peptide sequences that are essential for drug function but susceptible to potential in vivo cleavages. HRMS-based single ion monitoring (SIM) on a Q Exactive™ mass spectrometer was employed to improve assay specificity and sensitivity for DCP(SS) due to its poor fragmentation and low sensitivity with SRM detection. The assay has been validated for the protein drug in monkey serum using both surrogate peptides with excellent accuracy (within ±4.4%Dev) and precision (within 7.5%CV) with a lower limit of quantitation (LLOQ) at 10 ng mL⁻¹. The protein concentrations in monkey serum obtained from the DCP(SS)-based assay not only provided important pharmacokinetic parameters, but also confirmed in vivo stability of the peptide regions of interest by comparing drug concentrations with those obtained from the CP-based assay or from a ligand-binding assay (LBA). Furthermore, UHPLC-HRMS allowed simultaneous monitoring of the oxidized forms of both surrogate peptides to evaluate potential ex vivo/in vivo oxidation of one methionine present in each of both surrogate peptides. To the best of our knowledge, this is the first report of using a surrogate disulfide-containing peptide for LC-MS bioanalysis of a therapeutic protein.     

Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant)

This communication details the kilogram-scale synthesis of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238, auglurant), a novel mGlu₅ negative allosteric modulator (NAM) developed as an alternative treatment for depression. The process highlights a challenging pyridine N-oxidation sequence, an S_NAr reaction, and the elimination of all chromatography steps (required in the medicinal chemistry route) with replacement by highly efficient recrystallizations (save one silica plug). The improved process was utilized for the preparation of a 1.2 kg toxicology batch, as well as a 2.82 kg GMP batch to support the Phase I trial, in very high purity (99.8%).