An efficient and scalable process to produce morpholine-d8

Incorporation of isotopes has long been used as a research tool to label carbons and elucidate biochemical pathways. More recently, H→D exchange has led to analogs of therapeutic agents with improved metabolic stability and properties. Such compounds also have the potential for an improved drug/drug interaction profile and may even avoid the formation of toxic metabolites. Hence, a clear need for an efficient access to deuterated intermediates on large scale has emerged. In the context of an ongoing drug discovery program, we required large quantities of morpholine-d₈. We herein report the successful optimization of a one-pot process allowing a near complete exchange of all methylene hydrogens in morpholine to deuterium atoms using D₂O as the sole source of deuterium and Raney Nickel as catalyst. This facile and safe protocol will be used to scale up the synthesis of morpholine-d₈ in due course.     

The gas chromatography, thermal analysis and mass spectrometry of fluorinated lead β-diketonates Determination of traces of lead by the integrated ion-current technique

Preparative details for perfluoroalkanoylpivalylmethanes and their lead chelates are given. Thermal analysis, gas chromatography and mass spectral studies all indicate high thermal stability, but strong column interaction makes successful quantitative gas chromatography difficult. The integrated ion-current technique is applied to determine lead heptafluorobutanoylpivalylmethanate in the range 10^-9–10^-7 g of lead, but a lower detection limit of ca. 10^-14 g is indicated.     

Crystallisation kinetics,glass forming ability and thermal stability in glassy Se100 − xInx chalcogenide alloys

Differential scanning calorimetry (DSC) studies have been done under non-isothermal conditions at different heating rates for glassy Se_100 ? xIn_x (5 ≤ x ≤ 20) alloys. DSC traces with well-defined endothermic and exothermic troughs and peaks at glass transition (T_g), crystallisation (T_c) and melting (T_m) temperatures were observed. The crystallisation kinetics parameters, Avrami index (n), activation energy for crystallisation (E_c) and frequency factor (K_o), have been calculated on the basis of the classical Johnson–Mehl–Avrami (JMA) model and related methods derived by Kissinger, Augis–Bennett and Mahedevan. Activation energy for glass transformation (E_t) has been evaluated on the usual two different non-isothermal methods developed by Moynihan and Kissinger. An extension of the Augis–Bennett method well known for evaluating E_c to calculate E_t has been explored with satisfactory results. Results obtained from these methods are in close agreement with each other. Close correlation between E_t, E_c and heating rate (β) was observed. The glass forming ability (GFA) and thermal stability parameters have been calculated for each glass system. It was found that the proportion of indium additive changed significantly the values of glass/crystal transformation, GFA and thermal stability of the studied system.     

Nematic Liquid Crystals with a Trifluoromethyl Group

Abstract

We have synthesised a new class of compounds incorporating a trifluoromethyl group in the terminal alkoxy or alkenyloxy chain. Compounds containing several aromatic rings were synthesised with a view to producing compounds of high birefringence. This also included the synthesis of compounds containing a carbon-carbon triple bond. Compounds with three 1,4-disubstituted rings were synthesised in order to produce materials with a high nematic clearing point and as low a melting point as possible. Laterally fluoro-substituted compounds were prepared to generate a high positive value of the dielectric anisotropy, a low melting point and no smectic mesophases. Substances containing a cyclohexyl ring, which tend to induce a lower viscosity and compounds incorporating a bicyclo[2.2.2]octane ring were also synthesised in order to produce a high nematic clearing point and to influence the elastic constants. The (E)-trifluorobut-2-enyloxy-compounds were prepared in attempts to produce compounds with appropriate elastic constants and a high birefringence.     

Dual Gold‐Catalyzed Head‐to‐Tail Coupling of Iodoalkynes

Various haloalkynes are converted in the presence of a dual activation gold catalyst. Via a dual activation process a completely atom economic head‐to‐tail coupling delivers gem‐dihalogenated conjugated enynes as valuable building blocks for organic synthesis.     

Selective sampling using confocal Raman spectroscopy provides enhanced specificity for urinary bladder cancer diagnosis

In recent years, Raman spectroscopy has shown substantive promise in diagnosing bladder cancer, especially due to its exquisite molecular specificity. The ability to reduce false detection rates in comparison to existing diagnostic tools such as photodynamic diagnosis makes Raman spectroscopy particularly attractive as a complementary diagnostic tool for real-time guidance of transurethral resection of bladder tumor (TURBT). Nevertheless, the state-of-the-art high-volume Raman spectroscopic probes have not reached the expected levels of specificity thereby impeding their clinical translation. To address this issue, we propose the use of a confocal Raman probe for bladder cancer diagnosis that can boost the specificity of the diagnostic algorithm based on its suppression of the out-of-focus non-analyte-specific signals emanating from the neighboring normal tissue. In this article, we engineer and apply such a probe, having depth of field of approximately 280?μm, for Raman spectral acquisition from ex vivo normal and cancerous TURBT samples. Using this clinical dataset, a diagnostic algorithm based on principal component analysis and logistic regression is developed. We demonstrate that this approach results in comparable sensitivity but significantly higher specificity in relation to high-volume Raman spectral data. The application of only two principal components is sufficient for the discrimination of the samples underlining the robustness of the algorithm. Further, no discordance between replicate spectra is observed emphasizing the reproducible nature of the current diagnostic assessment. The high levels of sensitivity and specificity achieved in this proof-of-concept study opens substantive avenues for application of a confocal Raman probe during endoscopic procedures related to diagnosis and treatment of bladder cancer.

Buffers for the Physiological pH Range: Studies of 4-(N-Morpholino)butanesulfonic Acid (MOBS) from 5 to 55 °C

In this study, we report the pH values of two buffer solutions without chloride ion and eight buffer solutions with NaCl with an ionic strength I=0.16 mol?kg^?1. Electromotive force (emf) techniques have been used to get the cell potentials at 12 temperatures from 5 to 55?°C, including 37?°C. An extended form of the Bates-Guggenheim convention is used in the entire ionic strength range, 0.04 to 0.16?mol?kg^?1. The residual liquid junction potentials (??E _j ) of the buffer solutions of MOBS have been estimated from previous measurements with a flowing junction cell. These values of ??E _j have been used for correction in order to ascertain the operational pH values of four buffer solutions of MOBS at 25 and 37?°C. These solutions are recommended as pH standards for physiological application in the pH range 7.4 to 7.7.     

Asymmetric synthesis of β-fluoroaryl-β-amino acids

The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to a range of β-fluoroaryl-α,β-unsaturated esters gave the corresponding β-amino esters with high diastereoselectivity and in good isolated yields. Sequential treatment of the resultant β-fluoroaryl-β-amino esters under optimised hydrogenolysis conditions, followed by ester hydrolysis with 2.0 M aq HCl, provided access to a range of β-fluoroaryl-β-amino acids in good yield.     

Hydrogen bis[tris(4‐fluorophenyl)phosphane oxide] triiodide

In the title compound, C₃₆H₂₅F₆O₂P₂⁺·I₃⁻, hydrogen‐bonded [{(p‐FC₆H₄)₃PO}₂H]⁺ dimers assemble along the crystallographic c axis to form channels that house extended chains of triiodide anions. Although the I—I bond lengths of 2.9452 (14) and 2.9023 (15) Å are typical, the inter‐ion I...I distance of 3.5774 (10) Å is unusually short. A posteriori modelling of nonmerohedral twinning about (100) has been only partially successful, achieving a reduction in the maximum residual electron density from 5.28 to 3.24 e Å⁻³. The inclusion of two low‐occupancy I‐atom sites (total 1.7%), which can be interpreted as translational disorder of the triiodide anions along the channels, reduced the maximum residual electron density to 2.03 e Å⁻³. The minor fractional contribution volume of the nonmerohedral twin domains refined to 0.24 and simultaneous refinement of the inversion twin domains showed the crystal to be a 0.5:0.5 inversion twin.