Palladium extraction following metal-catalysed reactions : recent advances and applications in the pharmaceutical industry

Palladium-catalysed cross-coupling reactions are used extensively in the pharmaceutical industry. Therefore, the potential contamination of products with elemental impurities is an issue that any process chemist must consider in the design of a plant process. This is not only to meet regulatory limits, which is unequivocally the primary reason for metal scavenging, but also due to the high cost and limited supply of palladium, driving the need for recovery to recycle. This review addresses the current technologies for palladium removal from organic solutions, with selected examples of their successful application in industrial-scale processes for pharmaceutical production. Palladium scavengers have been categorised based on their mode of action: adsorption, extraction/precipitation and crystallisation, to provide a summary of the current state-of-the-art in metal removal. Practical considerations when choosing metal removal methods are briefly discussed, illustrating their intrinsic advantages and drawbacks

A mechanistic investigation of the N-hydroxyphthalimide catalyzed benzylic oxidation mediated by sodium chlorite

A detailed investigation into the mechanistic course of N-hydroxyphthalimide catalyzed oxidation of benzylic centers using sodium chlorite as the stoichiometric oxidant is reported. Through a combination of experimental, spectroscopic, and computational techniques, the transformation is interrogated, providing improved reaction conditions and an enhanced understanding of the mechanism. Performing the transformation in the presence of acetic acid or a pH 4.5 buffer leads to extended reaction times but improves the catalyst lifetime, leading to the complete consumption of the starting material. Chlorine dioxide is identified as the active oxidant that is able to oxidize the N-hydroxyphthalimide anion to the phthalimide-N-oxyl radical, the proposed catalytically active species, which is able to abstract a hydrogen atom from the substrate. A second molecule of chlorine dioxide reacts with the resultant radical and, after loss of hypochlorous acid, leads to the observed product. Through a broad variety of techniques including UV/vis, EPR and Raman spectroscopy, isotopic labeling, and the use of radical traps, evidence for the mechanism is presented that is supported through electronic structural calculations

A mechanistic investigation of the N-hydroxyphthalimide catalyzed benzylic oxidation mediated by sodium chlorite

A detailed investigation into the mechanistic course of a N-hydroxyphthalimide catalyzed oxidation of benzylic centers using sodium chlorite as the stoichiometric oxidant is reported. Through a combination of experimental, spectroscopic and computational techniques the transformation is interrogated providing improved reaction conditions and an enhanced understanding of the mechanism. Performing the transformation in the presence of acetic acid or a pH 4.5 buffer leads to extended reaction times but improves the catalyst lifetime leading to complete consumption of starting material. Chlorine dioxide is identified as the active oxidant which is able to oxidize the N-hydroxyphthalimide anion to the phthalimide-N-oxyl radical, the proposed catalytically active species, which is able to abstract a hydrogen atom from the substrate. A second molecule of chlorine dioxide reacts with the resultant radical, and after loss of hypochlorous acid, leads to the observed product. Through a broad variety of techniques including UV/vis, EPR and Raman spectroscopy, isotopic labelling and the use of radical traps evidence for the mechanism is presented which is supported through electronic structural calculations

Jugoslavija u međunarodnoj trgovini ribom, ribljim proizvodima i prerađevinama

Sulfonamides are profoundly important in pharmaceutical design. C–N cross-coupling of sulfonamides is an effective method for fragment coupling and structure–activity relationship (SAR) mining. However, cross-coupling of the important <i>N</i>-arylsulfonamide pharmacophore has been notably unsuccessful. Here, we present a solution to this problem via oxidative Cu-catalysis (Chan–Lam cross-coupling). Mechanistic insight has allowed the discovery and refinement of an effective cationic Cu catalyst to facilitate the practical and scalable Chan–Lam <i>N</i>-arylation of primary and secondary <i>N</i>-arylsulfonamides at room temperature. We also demonstrate utility in the large scale synthesis of a key intermediate to a clinical hepatitis C virus treatment

Unleashing the potential to electrify process chemistry: from bench to plant

Editorial - No abstract available

On the Use of Differential Scanning Calorimetry for Thermal Hazard Assessment of New Chemistry: Avoiding Explosive Mistakes

Differential scanning calorimetry (DSC) is increasingly used as evidence to support a favourable safety profile of novel chemistry, or to highlight the need for caution. DSC enables preliminary assessment of the thermal hazards of a potentially energetic compound. However, unlike other standard characterisation methods, which have well defined formats for reporting data, the current reporting of DSC results for thermal hazard assessment has shown concerning trends. Around half of all results in 2019 did not include experimental details required to replicate the procedure. Furthermore, analysis for thermal hazard assessment is often only conducted in unsealed crucibles, which could lead to misleading results and dangerously incorrect conclusions. We highlight the specific issues with DSC analysis of hazardous compounds currently in the organic chemistry literature and provide simple ‘best practice’ guidelines which will give chemists confidence in reported DSC results and the conclusions drawn from them

Computer vision for non-contact monitoring of catalyst degradation and product formation kinetics

We report a computer vision strategy for the extraction and colorimetric analysis of catalyst degradation and product-formation kinetics from video footage. The degradation of palladium(ii) pre-catalyst systems to form ‘Pd black’ is investigated as a widely relevant case study for catalysis and materials chemistries. Beyond the study of catalysts in isolation, investigation of Pd-catalyzed Miyaura borylation reactions revealed informative correlations between colour parameters (most notably ΔE, a colour-agnostic measure of contrast change) and the concentration of product measured by off-line analysis (NMR and LC-MS). The breakdown of such correlations helped inform conditions under which reaction vessels were compromised by air ingress. These findings present opportunities to expand the toolbox of non-invasive analytical techniques, operationally cheaper and simpler to implement than common spectroscopic methods. The approach introduces the capability of analyzing the macroscopic ‘bulk’ for the study of reaction kinetics in complex mixtures, in complement to the more common study of microscopic and molecular specifics