Is the formation of N-heterocyclic carbenes (NHCs) a feasible mechanism for the distillation of imidazolium ionic liquids?

We describe the synthesis of two tetrachloroindate ionic liquids used as probes to study the involvement of NHCs (N-heterocyclic carbenes) in the distillation of imidazolium derivatives. Atmospheric-pressure chemical ionization mass spectrometry (APCI-MS), electrospray ionization mass spectrometry (ESI-MS), atmospheric-pressure thermal desorption ion mass spectrometry (APTDI-MS) and laser-induced acoustic desorption (LIAD) were used to depict the possibility of the involvement of NHCs during the distillation process. Each type of imidazolium derivative showed a particular mechanism of distillation, pointing firmly to the dependence of both the cation and the anion natures to distil as ion pairs or NHCs. Ionic liquid 1-n-butyl-3-methylimidazolium tetrachloroindate (1a) exhibited a preference to distil as ion pairs, whereas 3,3'-(ethane-1,2-diyl)bis(1-methyimidazolium)bis-tetrachloroindate (1b) may react with the Lewis acid anion, affording a bidentate NHC complex to distil. Thermodynamics, quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses of the ionic liquid 1a were also conducted and helped understand the preference for ion pairs instead of NHCs. The performed theoretical calculations did not forwent the possibility of NHC formation; however, they clearly indicated the high stability of the anions (Lewis acids in nature) and also indicated that the possible reaction between NHC and the anion is not favoured. The calculated thermodynamic values were in accordance with the features observed by MS and indicated ion pairs as the feasible species for the distillation of imidazolium-based ionic liquids.

Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients.

We present a comprehensive review of the advent and impact of continuous flow chemistry with regard to the synthesis of natural products and drugs, important pharmaceutical products and definitely responsible for a revolution in modern healthcare. We detail the beginnings of modern drugs and the large scale batch mode of production, both chemical and microbiological. The introduction of modern continuous flow chemistry is then presented, both as a technological tool for enabling organic chemistry, and as a fundamental research endeavor. This part details the syntheses of bioactive natural products and commercial drugs.

Antioxidative, Antiproliferative and Antimicrobial Activities of Phenolic Compounds from Three Myrcia Species.

Myrcia bella Cambess., Myrcia fallax (Rich.) DC. and Myrcia guianensis (Aubl.) DC. (Myrtaceae) are trees found in Brazilian Cerrado. They have been widely used in folk medicine for the treatment of gastrointestinal disorders, hemorrhagic and infectious diseases. Few reports have been found in the literature connecting their phenolic composition and biological activities. In this regard, we have profiled the main phenolic constituents of Myrcia spp. leaves extracts by ESI(−)Q-TOF-MS. The main constituents found were ellagic acid (M. bella), galloyl glucose isomers (M. guianensis) and hexahydroxydiphenic (HHDP) acid derivatives (M. fallax). In addition, quercetin and myricetin derivatives were also found in all Myrcia spp. extracts. The most promising antioxidant activity, measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity, was found for M. fallax extracts (EC50 8.61 ± 0.22 µg·mL−1), being slightly less active than quercetin and gallic acid (EC50 2.96 ± 0.17 and 2.03 ± 0.02 µg·mL−1, respectively). For in vitro antiproliferative activity, M. guianensis showed good activity against leukemia (K562 TGI = 7.45 µg·mL−1). The best antimicrobial activity was observed for M. bella and M. fallax to Escherichia coli (300 and 250 µg·mL−1, respectively). In conclusion, the activities found are closely related to the phenolic composition of these plants.

Charge Tags for Most Comprehensive ESI-MS Monitoring of Morita-Baylis-Hillman (MBH)/aza-MBH Reactions: Solid Mechanistic View and the Dualistic Role of the Charge Tagged Acrylate.

Neutral and charge tagged reagents were used to investigate the mechanism of the classical Morita-Baylis-Hillman (MBH) reaction as well as its aza-version using mass spectrometry with electrospray ionization (ESI-MS). The use of an acrylate (activated alkene) with a methylimidazolium ion as a charge tag eliminates the requirement for adding acids as ESI(+) additives, which are normally used to favor protonation and therefore detection of reaction partners (reagents, intermediates, and products) by ESI(+)-MS. For both charge tagged reactions (MBH/aza-MBH), most reactants, intermediates, and the final adducts were efficiently detected in the form of abundant doubly and singly charged ions. Characterization of the reactions partners was performed via both tandem mass spectrometry (ESI(+)-MS/MS) and accurate m/z measurements. The charge tagged reactions also showed faster conversion rates when compare to the neutral reaction, indicating a dualistic role for the charge tagged acrylate. It acts as both the reagent and a cocatalyst due to the inherent ionic-coordination nature of the methylimidazolium ion, which stabilizes the zwitterionic intermediates and reagents through different types of coordination ion pairs. Hemiacetal intermediates for the rate-limiting proton transfer step were also intercepted and characterized for both classical and aza-MBH charge tagged reactions.

Genomic and chemical insights into biosurfactant production by the mangrove-derived strain Bacillus safensis CCMA-560.

Many Bacillus species can produce biosurfactant, although most of the studies on lipopeptide production by this genus have been focused on Bacillus subtilis. Surfactants are broadly used in pharmaceutical, food and petroleum industry, and biological surfactant shows some advantages over the chemical surfactants, such as less toxicity, production from renewable, cheaper feedstocks and development of novel recombinant hyperproducer strains. This study is aimed to unveil the biosurfactant metabolic pathway and chemical composition in Bacillus safensis strain CCMA-560. The whole genome of the CCMA-560 strain was previously sequenced, and with the aid of bioinformatics tools, its biosurfactant metabolic pathway was compared to other pathways of closely related species. Fourier transform infrared (FTIR) and high-resolution TOF mass spectrometry (MS) were used to characterize the biosurfactant molecule. B. safensis CCMA-560 metabolic pathway is similar to other Bacillus species; however, some differences in amino acid incorporation were observed, and chemical analyses corroborated the genetic results. The strain CCMA-560 harbours two genes flanked by srfAC and srfAD not present in other Bacillus spp., which can be involved in the production of the analogue gramicidin. FTIR and MS showed that B. safensis CCMA-560 produces a mixture of at least four lipopeptides with seven amino acids incorporated and a fatty acid chain with 14 carbons, which makes this molecule similar to the biosurfactant of Bacillus pumilus, namely, pumilacidin. This is the first report on the biosurfactant production by B. safensis, encompassing the investigation of the metabolic pathway and chemical characterization of the biosurfactant molecule.

Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin.

An integrated batch and continuous flow process has been developed for the gram-scale synthesis of goniothalamin. The synthetic route hinges upon a telescoped continuous flow Grignard addition followed by an acylation reaction capable of delivering a racemic goniothalamin precursor (16) (20.9 g prepared over 3 h), with a productivity of 7 g·h-1. An asymmetric Brown allylation protocol was also evaluated under continuous flow conditions. This approach employing (-)-Ipc2B(allyl) provided an (S)-goniothalamin intermediate in 98% yield and 91.5% enantiomeric excess (ee) with a productivity of 1.8 g·h-1. For the final step, a ring-closing metathesis reaction was explored under several conditions in both batch and flow regimes. In a batch operation, the Grubbs second-generation was shown to be effective and highly selective for the desired ring closure product over those arising from other modes of reactivity, and the reaction was complete in 1.5 h. In a flow operation, reactivity and selectivity were attenuated relative to the batch mode; however, after further optimization, the residence time could be reduced to 16 min with good selectivity and good yield of the target product. A tube-in-tube reactor was investigated for in-situ ethylene removal to favor ring-closing over cross-metathesis, in this context. These results provide further evidence of the utility of flow chemistry for organometallic processing and reaction telescoping. Using the developed integrated batch and flow methods, a total of 7.75 g of goniothalamin (1) was synthesized.

Unusual mechanisms in Claisen rearrangements: an ionic fragmentation leading to a meta-selective rearrangement.

A mechanistic investigation of the acid-catalysed redox-neutral oxoarylation reaction of ynamides using electrospray ionisation mass-spectrometry (ESI-MS) and quantum chemical calculations (DFT and MP2) is presented. This study reveals the diversity of pathways and products available from an otherwise deceptively simple-looking, classical transformation: fragmentation, an unusual meta-arylation and competing α-carbonyl cation pathways are some of the alternatives unveiled by ESI-MS and mechanistic experiments. Detailed calculations explain the observed trends and rationalise the results.

Guaianolide sesquiterpene lactones and aporphine alkaloids from the stem bark of Guatteria friesiana.

Three guaianolide sesquiterpenes, denoted guatterfriesols A-C, and four aporphine alkaloid derivatives were isolated from the stem bark of the Amazonian plant Guatteria friesiana. Thus far, sesquiterpene lactones have not been described in Annonaceae. Structures of the previously undescribed compounds were established by using 1D and 2D NMR spectroscopy in combination with MS. The absolute stereochemistry was assigned via NOE NMR experiments, ECD spectroscopy, and theoretical calculations using the TDDFT approach. Among the isolated compounds, the alkaloid guatterfriesidine showed anti-glycation activity by inhibiting the formation of advanced glycation end-products (AGEs) through the prevention of oxidation in both BSA/methylglyoxal and BSA/fructose systems.

Direct Visualization of Neurotransmitters in Rat Brain Slices by Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI - MS).

Mass spectrometry imaging (MSI) of neurotransmitters has so far been mainly performed by matrix-assisted laser desorption/ionization (MALDI) where derivatization reagents, deuterated matrix and/or high resolution, or tandem MS have been applied to circumvent problems with interfering ion peaks from matrix and from isobaric species. We herein describe the application of desorption electrospray ionization mass spectrometry imaging (DESI)-MSI in rat brain coronal and sagittal slices for direct spatial monitoring of neurotransmitters and choline with no need of derivatization reagents and/or deuterated materials. The amino acids γ-aminobutyric (GABA), glutamate, aspartate, serine, as well as acetylcholine, dopamine, and choline were successfully imaged using a commercial DESI source coupled to a hybrid quadrupole-Orbitrap mass spectrometer. The spatial distribution of the analyzed compounds in different brain regions was determined. We conclude that the ambient matrix-free DESI-MSI is suitable for neurotransmitter imaging and could be applied in studies that involve evaluation of imbalances in neurotransmitters levels. Graphical Abstract ᅟ.

Vapors from Ionic Liquids: Reconciling Simulations with Mass Spectrometric Data.

The species involved in the distillation of aprotic ionic liquids are discussed in light of recent simulations and mass spectrometric data obtained by various techniques. New mass spectrometric data collected via laser-induced acoustic desorption and the thermal desorption of ionic liquids are also presented as well as additional DFT calculations. The available evidence of theoretical simulations and mass spectrometric data suggests that the distillation of ionic liquids occurs mainly via neutral ion pairs of composition CnAn [C(+) = cation and A(-) = anion], followed by gas-phase dissociation to lower order ion pairs and then dissociation of hot CA to C(+) and A(-), followed by ion/molecule association events to give [CnAn-1](+) or [Cn-1An](-) ions to a degree that depends on the amount of internal energy deposited into the neutral CnAn clusters upon evaporation.