Synthesis and reactivity of laquinimod, a quinoline-3-carboxamide: intramolecular transfer of the enol proton to a nitrogen atom as a plausible mechanism for ketene formation

5-Chloro-N-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinolinecarboxamide (laquinimod, 2) is an oral drug in clinical trials for the treatment of multiple sclerosis. The final step in the synthesis of 2 is a high-yielding aminolysis reaction of ester 1 with N-ethylaniline. An equilibrium exists between 1 and 2, and removal of formed methanol during the reaction is a prerequisite for obtaining high yields of 2 from 1. The reactivity of 1 and 2 is explained by a mechanistic model that involves a transfer of the enol proton to the exocyclic carbonyl substituent with concomitant formation of ketene 3. This proton transfer is especially facilitated for 2 because the intramolecular hydrogen bond to the carbonyl oxygen is weakened due to steric interactions. Both 1 and 2 undergo solvolosis reactions that obey first-order reaction kinetics, further supporting the theory that these two molecules are able to decompose unimolecularly into ketene 3. The solvent-dependent spectroscopic features of 2 indicate that the molecule mainly resides in two conformations. One conformation is favored in nonpolar solvents and is likely the result of intramolecular hydrogen bonding. The other conformation is favored in polar solvents and probably exhibits less intramolecular hydrogen bonding.     

Synthesis of a C-glycoside analogue of beta-D-galactosyl hydroxylysine and incorporation in a glycopeptide from type II collagen

A stereoselective synthesis of the C-glycoside analogue of beta-D-galactosyl-(5R,2S)-hydroxylysine (1) has been achieved starting from tetra-O-benzyl-D-galactopyranosyl lactone. The synthesis involved establishment of three stereogenic centers in an unambiguous manner. A facially selective Grignard reaction followed by a silane reduction was used for the anomeric position of the C-galactose residue. An Evans allylation established the configuration of the delta-aminomethylene group of the hydroxylysine moiety, whereas an asymmetric hydrogenation utilizing Burk's catalyst was used for the alpha-amino acid moiety itself. The synthesis was completed in 17 steps with an overall yield of 18%, resulting in the most complex and functionalized C-glycoside analogue of a naturally occurring glycosylated amino acid prepared to date. In addition, amino acid 1 was incorporated in a glycopeptide from type II collagen known to be crucial for the response of autoimmune T cells obtained in models of rheumatoid arthritis. A preliminary immunological study revealed that four out of five members in a panel of T cell hybridomas were able to recognize this C-linked glycopeptide when presented by A(q) class II MHC molecules.     

Synthesis of the spiroketal fragment of bistramide A via an exocyclic enol ether

An efficient synthesis of the spirocyclic fragment 1 of bistramides is reported. An olefination reaction of lactone 4 with sulfone 5 gave the enol ether 3, which upon cyclization in acidic media provided the spiroketal ring system. This compound was then converted into the C19-C36 fragment of the bistramides via successive Julia-Kocienski and Horner-Emmons olefinations.     

Tribological behaviour of nanostructured Ti-C:H coatings for biomedical applications

The development of a mechanically stable, functionally graded Ti-doped a-C:H interface layer in combination with a functional a-C:H coating requires a reduction of the brittle phases which induce generally problems in the transitions from Ti to TiC/a-C:H. The core objective of this study was to develop an optimum interlayer between the substrate and the functional top layer for biomedical applications, namely for tooth implants. Since the interlayer may be exposed to the sliding process, in the case of local failure of the top layer it has to fulfil the same criteria: biocompatibility, high wear resistance and low friction.The functional Ti-C:H layers with thickness in the range 2.5–3.5 μm were deposited by a magnetron sputtering/PECVD hybrid process by sputtering a Ti-target in a C₂H₂ + Ar atmosphere in dc discharge regime. The sets of coating samples were prepared by varying the C and H concentrations controlled by the C₂H₂ flow during the deposition process. The tribological properties were evaluated on a pin-on-disc tribometer at room temperature (RT) and at 100 °C using 440C balls with a diameter of 6 mm. The tests at 100 °C were performed to investigate the effect of the sterilization temperature on the tribological properties and the coating lifetime as well. The tribological performance was examined with respect to the friction coefficient, the wear rates of the coating and the counter-parts and the analysis of the wear debris. The Ti/C ratio decreased almost linearly from 4.5 to 0.1 with increasing C₂H₂ flow; the hydrogen content showed a minimum of 5 at.% at C₂H₂ flow of 30 sccm, while for lower flows it was about 10 at.%. The coatings could be divided into three groups based on the C₂H₂ flow: (i) 10–15 sccm, exhibiting severe abrasive damage during the sliding tests, (ii) 20–45 sccm, showing the highest hardness and friction values, and (iii) 52–60 sccm, with moderate hardness and minimal values of the friction coefficient and the wear rate.     

Enclosing all zeros of an analytic function — A rigorous approach

We present a method to find all zeros of an analytic function in a rectangular domain. The approach is based on finding guaranteed enclosures rather than approximations of the zeros. Well-isolated simple zeros are determined fast and with high accuracy. Clusters of zeros can in many cases be distinguished from multiple zeros by applying the argument principle to sufficiently high-order derivatives of the function. We illustrate the proposed method through five examples of varying levels of complexity.     

Time-domain noise reduction based on an orthogonal decomposition for desired signal extraction

This paper addresses the problem of noise reduction in the time domain where the clean speech sample at every time instant is estimated by filtering a vector of the noisy speech signal. Such a clean speech estimate consists of both the filtered speech and residual noise (filtered noise) as the noisy vector is the sum of the clean speech and noise vectors. Traditionally, the filtered speech is treated as the desired signal after noise reduction. This paper proposes to decompose the clean speech vector into two orthogonal components: one is correlated and the other is uncorrelated with the current clean speech sample. While the correlated component helps estimate the clean speech, it is shown that the uncorrelated component interferes with the estimation, just as the additive noise. Based on this orthogonal decomposition, the paper presents a way to define the error signal and cost functions and addresses the issue of how to design different optimal noise reduction filters by optimizing these cost functions. Specifically, it discusses how to design the maximum SNR filter, the Wiener filter, the minimum variance distortionless response (MVDR) filter, the tradeoff filter, and the linearly constrained minimum variance (LCMV) filter. It demonstrates that the maximum SNR, Wiener, MVDR, and tradeoff filters are identical up to a scaling factor. It also shows from the orthogonal decomposition that many performance measures can be defined, which seem to be more appropriate than the traditional ones for the evaluation of the noise reduction filters.     

Determination of Diaryliodonium Species by Reverse Iodometric Titration with Ascorbic Acid

Diaryliodonium salts are used in organic chemistry, materials science and pharmaceutical chemistry. For the quantitative analysis of diaryliodonium salts, only instrumentally demanding techniques requiring highly skilled operators are available. Surprisingly, no titration method taking advantage of the oxidising ability of diaryliodonium is available in the literature. In the present work, a titration method for the determination of diaryliodonium salts is presented. It is based on the reaction of diaryliodonium species with ascorbic acid, whose excess is subsequently determined by means of iodometric potentiometric titration. Application of the protocol to various diaryliodonium salts revealed the scope and limitations of the method.     

A gravity-independent single-phase electrode reservoir for capillary electrophoresis applications

Capillary electrophoresis (CE) holds great promise as an in situ analytical technique for a variety of applications. However, typical instrumentation operates with open reservoirs (e.g., vials) to accommodate reagents and samples, which is problematic for automated instruments designed for space or underwater applications that may be operated in various orientations. Microgravity conditions add an additional challenge due to the unpredictable position of the headspace (air layer above the liquid) in any two-phase reservoir. One potential solution for these applications is to use a headspace-free, flow-through reservoir design that is sealed and connected to the necessary reagents and samples. Here, we demonstrate a flow-through high-voltage (HV) reservoir for CE that is compatible with automated in situ exploration needs, and which can be electrically isolated from its source fluidics (in order to prevent unwanted leakage current). We also demonstrate how the overall system can be rationally designed based on the operational parameters for CE to prevent electrolysis products generated at the electrode from entering the capillary and interfering with the CE separation. A reservoir was demonstrated with a 19 mm long, 1.8 mm inner diameter channel connecting the separation capillary and the HV electrode. Tests of these reservoirs integrated into a CE system show reproducible CE system operation with a variety of background electrolytes at voltages up to 25 kV. Rotation of the reservoirs, and the system, showed that their performance was independent of the direction of the gravity vector.     

A Deep-Blue-Emitting Heteroatom-Doped MR-TADF Nonacene for High-Performance Organic Light-Emitting Diodes**

We present a p- and n-doped nonacene compound, NOBNacene, that represents a rare example of a linearly extended ladder-type multiresonant thermally activated delayed fluorescence (MR-TADF) emitter. This compound shows efficient narrow deep blue emission, with a λ_PL of 410 nm, full width at half maximum, FWHM, of 38 nm, photoluminescence quantum yield, Φ_PL of 71 %, and a delayed lifetime, τ_d of 1.18 ms in 1.5 wt % TSPO1 thin film. The organic light-emitting diode (OLED) using this compound as the emitter shows a comparable electroluminescence spectrum peaked at 409 nm (FWHM=37 nm) and a maximum external quantum efficiency (EQE_max) of 8.5 % at Commission Internationale de l’Éclairage (CIE) coordinates of (0.173, 0.055). The EQE_max values were increased to 11.2 % at 3 wt % doping of the emitter within the emissive layer of the device. At this concentration, the electroluminescence spectrum broadened slightly, leading to CIE coordinates of (0.176, 0.068).