Role of Steric Hindrance in the Newman-Kwart Rearrangement and in the Synthesis and Photophysical Properties of Arylsulfanyl Tetrapyrazinoporphyrazines

Conditions for the Newman-Kwart rearrangement of phenols into thiophenols were investigated in relation to the bulkiness of substituents at the 2 and 6 positions of the starting phenol derivative with an emphasis on eliminating side reactions. Thiophenols with different 2,6-disubstitution patterns (including hydrogen, methyl, isopropyl or <i>tert</i>-butyl groups) were used for the synthesis of 5,6-bis­(arylsulfanyl)­pyrazine-2,3-dicarbonitriles that underwent cyclotetramerization leading to the corresponding zinc tetrapyrazinoporphyrazines (TPyzPz), aza-analogues of phthalocyanines. Several methods for the cyclotetramerization were attempted to eliminate problematic side reactions. Magnesium butoxide was found as the most suitable cyclotetramerization agent and afforded TPyzPzs in reasonable yields of approximately 30% under mild conditions. The varying arrangements of the peripheral substitutions resulting from the different bulkiness of the substituents were demonstrated by the X-ray structures of the pyrazine-2,3-dicarbonitriles. The prepared zinc arylsulfanyl TPyzPzs showed an absorption maximum at a Q-band over 650 nm, fluorescence quantum yields between 0.078 and 0.20, and singlet oxygen quantum yields ranging 0.58–0.69. TPyzPzs with isopropyl groups were found to be the best derivatives in this series as they combined facile cyclotetramerization, no aggregation, and good photophysical properties, which makes them potentially suitable for photodynamic therapy

Role of Steric Hindrance in the Newman-Kwart Rearrangement and in the Synthesis and Photophysical Properties of Arylsulfanyl Tetrapyrazinoporphyrazines

Conditions for the Newman-Kwart rearrangement of phenols into thiophenols were investigated in relation to the bulkiness of substituents at the 2 and 6 positions of the starting phenol derivative with an emphasis on eliminating side reactions. Thiophenols with different 2,6-disubstitution patterns (including hydrogen, methyl, isopropyl or <i>tert</i>-butyl groups) were used for the synthesis of 5,6-bis­(arylsulfanyl)­pyrazine-2,3-dicarbonitriles that underwent cyclotetramerization leading to the corresponding zinc tetrapyrazinoporphyrazines (TPyzPz), aza-analogues of phthalocyanines. Several methods for the cyclotetramerization were attempted to eliminate problematic side reactions. Magnesium butoxide was found as the most suitable cyclotetramerization agent and afforded TPyzPzs in reasonable yields of approximately 30% under mild conditions. The varying arrangements of the peripheral substitutions resulting from the different bulkiness of the substituents were demonstrated by the X-ray structures of the pyrazine-2,3-dicarbonitriles. The prepared zinc arylsulfanyl TPyzPzs showed an absorption maximum at a Q-band over 650 nm, fluorescence quantum yields between 0.078 and 0.20, and singlet oxygen quantum yields ranging 0.58–0.69. TPyzPzs with isopropyl groups were found to be the best derivatives in this series as they combined facile cyclotetramerization, no aggregation, and good photophysical properties, which makes them potentially suitable for photodynamic therapy

Scalable Synthesis of Human Ultralong Chain Ceramides

Ceramides with ultralong chains (≥30 carbons), also known as acylceramides, play a critical role in the survival of mammals on dry land. An efficient and scalable synthesis of four major classes of ultralong human skin ceramides is reported. The key approach involves the use of a succinimidyl ester that acts as a protective group, helps overcome the extremely low solubility, and simultaneously activates the fatty acid for its clean and high-yielding attachment to a sphingoid base

Conventional-Flow Liquid Chromatography–Mass Spectrometry for Exploratory Bottom-Up Proteomic Analyses

Due to its sensitivity and productivity, bottom-up proteomics based on liquid chromatography–mass spectrometry (LC–MS) has become the core approach in the field. The <i>de facto</i> standard LC–MS platform for proteomics operates at sub-μL/min flow rates, and nanospray is required for efficiently introducing peptides into a mass spectrometer. Although this is almost a “dogma”, this view is being reconsidered in light of developments in highly efficient chromatographic columns, and especially with the introduction of exceptionally sensitive MS instruments. Although conventional-flow LC–MS platforms have recently penetrated targeted proteomics successfully, their possibilities in discovery-oriented proteomics have not yet been thoroughly explored. Our objective was to determine what are the extra costs and what optimization and adjustments to a conventional-flow LC–MS system must be undertaken to identify a comparable number of proteins as can be identified on a nanoLC–MS system. We demonstrate that the amount of a complex tryptic digest needed for comparable proteome coverage can be roughly 5-fold greater, providing the column dimensions are properly chosen, extra-column peak dispersion is minimized, column temperature and flow rate are set to levels appropriate for peptide separation, and the composition of mobile phases is fine-tuned. Indeed, we identified 2 835 proteins from 2 μg of HeLa cells tryptic digest separated during a 60 min gradient at 68 μL/min on a 1.0 mm × 250 mm column held at 55 °C and using an aqua–acetonitrile mobile phases containing 0.1% formic acid, 0.4% acetic acid, and 3% dimethyl sulfoxide. Our results document that conventional-flow LC–MS is an attractive alternative for bottom-up exploratory proteomics