Triflate-Selective Suzuki Cross-Coupling of Chloro- and Bromoaryl Triflates Under Ligand-Free Conditions.

In the absence of strong ancillary ligands such as phosphines or N-heterocyclic carbenes, palladium salts are selective for C-OTf cleavage in the room-temperature Suzuki couplings of chloroaryl triflates in acetonitrile. Similar "ligand-free" conditions in DMSO also promote triflate-selective Suzuki coupling of bromoaryl triflates. This triflate selectivity complements the typical preference for reaction of bromides in prior reports of Suzuki couplings using phosphine ligands. DFT calculations and additional experimental evidence are consistent with triflate-selective oxidative addition taking place at homogeneous, possibly mononuclear, anionic palladium supported by a solvent molecule.

Classification and Quantification of Microplastics (<100 µm) Using a Focal Plane Array-Fourier Transform Infrared Imaging System and Machine Learning.

Microplastics are defined as microscopic plastic particles in the range from few micrometers and up to 5 mm. These small particles are classified as primary microplastics when they are manufactured in this size range, whereas secondary microplastics arise from the fragmentation of larger objects. Microplastics are widespread emerging pollutants, and investigations are underway to determine potential harmfulness to biota and human health. However, progress is hindered by the lack of suitable analytical methods for rapid, routine, and unbiased measurements. This work aims to develop an automated analytical method for the characterization of small microplastics (<100 µm) using micro-Fourier transform infrared (µ-FTIR) hyperspectral imaging and machine learning tools. Partial least squares discriminant analysis (PLS-DA) and soft independent modeling of class analogy (SIMCA) models were evaluated, applying different data preprocessing strategies for classification of nine of the most common polymers produced worldwide. The hyperspectral images were also analyzed to quantify particle abundance and size automatically. PLS-DA presented a better analytical performance in comparison with SIMCA models with higher sensitivity, sensibility, and lower misclassification error. PLS-DA was less sensitive to edge effects on spectra and poorly focused regions of particles. The approach was tested on a seabed sediment sample (Roskilde Fjord, Denmark) to demonstrate the method efficiency. The proposed method offers an efficient automated approach for microplastic polymer characterization, abundance numeration, and size distribution with substantial benefits for method standardization.

Characterizing structures, energetics, and spectra of species on the 1,3[H, C, As] potential energy surfaces: A high-level theoretical contribution.

The ground and the low lying electronic states of structures on the 1,3[H, C, As] potential energy surfaces were investigated with the highly correlated theoretical approaches CCSD(T), CCSD(T)-F12b, and CASSCF/MRCI along with the series of correlation consistent (aug-cc-pVnZ, n = D, T, Q, 5) basis sets. Energetic and spectroscopic parameters were obtained at the complete basis set limit, and the effect of core-valence correlation on these properties evaluated. Fundamental frequencies were also computed with the variational configuration interaction (VCI) approach. Heats of formation at 0 and 298.15 K were estimated for HCAs and CH, AsH, CAs, and HCAs, as well as the calculation of ionization potentials for HCAs. Comparisons of the present results with literature ones for the systems HCN/HNC, HCP/HPC highlight similarities and differences among these systems. Altogether, this investigation provides a very reliable characterization of the species on the surfaces and should guide future experimental studies on these systems.

Evaluation of chemometric approaches for polymorphs quantification in tablets using near-infrared hyperspectral images.

Near-Infrared hyperspectral imaging (HSI-NIR) is a useful technique for pharmaceutical research and industry alike. It can provide important surface information such as the polymorphs quantification and its distribution over the tablet. Several chemometric tools are applied for this purpose, with MCR-ALS and PLS regression being the most common approaches. In this work, a detailed comparison between these two approaches is performed. Beyond a "simple" regression comparison, a comparison of the score images (local quantification) was also evaluated. The system under study is tablets with ternary mixtures of Mebendazol (MBZ) polymorphs, microcrystalline cellulose and magnesium stearate. PLS models, in general, gave lower RMSEP (below 1.7% w/w for the three MBZ polymorphs) than the corresponding MCR-ALS predictions. Analyzing the distributions of the scores in the images of each sample shows clear differences between the PLS and MCR-ALS models. The MCR-ALS gave more chemical meaningful distribution maps for all polymorphs, even though the PLS accurately predicts the average concentration across the image. The problem is that the PLS models used the main spectral regions to quantify each MBZ polymorph, but at the same time undermines the minor spectroscopic changes caused by the different polymorphs. Although this may seem as a minor deviation from the truth, the results clearly show that this deviation is detrimental for the analysis of the spatial distribution of the analytes. These results indicate that the optimal multivariate model for multivariate images depend on the goal of the analysis: global quantification or a distribution analysis.

Enantioselective, Noncovalent, Substrate-Directable Heck-Matsuda and Oxidative Heck Arylations of Unactivated Five-Membered Carbocyclic Olefins.

Highly diastereo- and enantioselective, noncovalent, substrate-directable Heck desymmetrizations of cyclopentenyl olefins containing hydroxymethyl and carboxylate functional groups are presented. These conformationally unbiased cyclic olefins underwent effective arylations in yields of up to 97 %, diastereoselectivity up to >20:1, and enantiomeric excesses of up to 99 %. Noncovalent directing effects were shown to be prevalent in both Heck-Matsuda and oxidative Heck reactions, allowing the preferential formation of cis-substituted aryl cyclopentenes containing two stereocenters, including quaternary stereocenters. These results further validate the internal out-of-coordination-sphere ion-dipole interaction concept directing the reaction diastereoselectivity to the cis-Heck product. This approach is complementary to existing methods using bis-phosphine monoxide ligands to give the opposite trans-diastereoisomer. The applicability of the method is showcased by the straightforward synthesis of a potent phosphodiesterase 4 inhibitor in a diastereo- and enantioselective manner. The reaction is operationally simple and has broad scope with regard to the nature of the arenediazonium salt and boronic acid employed. The mechanism and origin of stereoselectivity were investigated with control experiments and DFT calculations that fully supported the stabilizing internal out-of-coordination-sphere ion-dipole interaction between the resident functional group and cationic palladium.

Comparison of macro and micro Raman measurement for reliable quantitative analysis of pharmaceutical polymorphs.

This work reports on the use of micro- and macro-Raman measurements for quantification of mebendazole (MBZ) polymorphs A, B, and C in mixtures. Three Raman spectrophotometers were studied with a laser spot size of 3, 80 and 100 µm and spectral resolutions of 3.9, 9 and 4 cm-1, respectively. The samples studied were ternary mixtures varying the MBZ polymorphs A and C from 0 to 100% and polymorph B from 0 to 30%. Partial Least Squares (PLS) regression models were developed using the pre-processing spectra (2nd derivative) of the ternary mixtures. The best performance was obtained when the macro-Raman configuration was applied, obtaining RMSEP values of 1.68%, 1.24% and 2.03% w/w for polymorphs A, B, and C, respectively. In general, micro-Raman presented worst results for MBZ polymorphs prediction because the spectra obtained with this configuration does not represent the bulk proportion of mixtures, which have different particle morphologies and sizes. In addition, the influence of these particle features on micro-Raman measurements was also studied. Finally, the results demonstrated that reliable analytical quantifying of MBZ polymorphs can be reached using a laser with wider area illuminated, thus enabling acquisition of more reproductive and representative spectra of the mixtures.

Nickel-catalysed direct C2-arylation of N-heterocyclic carbenes.

A highly efficient nickel catalysed method for the direct C2-arylation of N-heterocyclic carbenes (NHCs) is reported. This protocol enables a facile access to C2-arylated imidazolium salts (NHC-Ar)X (X = Cl, Br, I or OTf). Experimental and theoretical studies suggest the viability of a Ni(i)/Ni(ii) catalytic pathway in which the dinuclear Ni(i) species [(NHC)NiX]2 plays a key role.

Theoretical study on selectivity trends in (N-heterocyclic carbene)-Pd catalyzed mizoroki-heck reactions: Exploring density functionals methods and molecular models.

The regioselectivity of the NHC-Pd catalyzed Heck coupling reaction between phenyl bromide and styrene has been investigated using the density functional theory, wave-function (WF)-based methods and two different sizes of model ligands. In addition to the WF methods, the TPSS-D3, ω B97X-D, BP86-D3, and M06-L density functionals were reliable approaches to be applied, independently of the basis set. Moreover, the NCI analysis showed that weak interactions are important forces to be taken into account when exploring the regioselectivity of this reaction, mainly when a crowded NHC ligand is present. © 2017 Wiley Periodicals, Inc.

Multivariate quantification of mebendazole polymorphs by terahertz time domain spectroscopy (THZ-TDS).

This work presents an analytical method based on terahertz-time domain spectroscopy (THz-TDS) and partial least squares (PLS) regression models to quantify mebendazole (MBZ) polymorphs (forms A, B and C) in pharmaceutical raw material. Mebendazole polymorphs A, B and C were quantified with RMSEP values of 1.5% w/w, 1.2% w/w and 1.8% w/w, respectively. The limits of detection (LOD) ranges obtained with the best PLS regression models were 2.7-4.3% w/w, 2.9-4.0% w/w and 2.4-3.1% w/w, for polymorphs A, B and C, respectively. This analytical performance is better than those for the methods described in the literature using near (NIR) and middle (MIR) infrared spectroscopies. The main advantage of THz spectroscopy is its ability to access directly information related to crystal lattices. According to the results, the developed method is a powerful technique for the quantification of MBZ polymorphs in raw material. This methodology can be implemented as a Process Analytical Technology (PAT) tool for quality control of pharmaceutical feedstock.

Intermolecular Noncovalent Hydroxy-Directed Enantioselective Heck Desymmetrization of Cyclopentenol: Computationally Driven Synthesis of Highly Functionalized cis-4-Arylcyclopentenol Scaffolds.

New computationally driven protocols for the Heck desymmetrization of 3-cyclopenten-1-ol with aryldiazonium tetrafluoroborates were developed. These new conditions furnished remarkable product selectivity originating from a resident hydroxyl group and the critical choice of the reaction solvent. Mechanistic insights gleaned from theoretical calculations of the putative transition states predicted toluene as an adequate solvent choice to attain high enantioselectivity by strengthening the noncovalent interaction of the substrate hydroxyl group and the chiral cationic palladium catalyst. Laboratory experiments validated the theoretical predictions, and by employing 2% MeOH/toluene as solvent, the Heck-Matsuda reaction provided exclusively the cis-4-arylcyclopentenols 3a-l in good to excellent yields in enantiomeric excesses up to 99%. The performance of the new PyOx ligand (S)-4-tert-butyl-2-(3,5-dichloropyridin-2-yl)-4,5-dihydrooxazole was also successfully evaluated in the Heck-Matsuda desymmetrization of 3-cyclopenten-1-ol. The synthetic potential of these highly functionalized cis-4-arylcyclopentenols is illustrated by a gold-catalyzed synthesis of cyclopenta[b]benzofuran skeletons.

Quantitative analysis of mebendazole polymorphs in pharmaceutical raw materials using near-infrared spectroscopy.

This work evaluates the feasibility of using NIR spectroscopy for quantification of three polymorphs of mebendazole (MBZ) in pharmaceutical raw materials. Thirty ternary mixtures of polymorphic forms of MBZ were prepared, varying the content of forms A and C from 0 to 100% (w/w), and for form B from 0 to 30% (w/w). Reflectance NIR spectra were used to develop partial least square (PLS) regression models using all spectral variables and the variables with significant regression coefficients selected by the Jack-Knife algorithm (PLS/JK). MBZ polymorphs were quantified with RMSEP values of 2.37% w/w, 1.23% w/w and 1.48% w/w for polymorphs A, B and C, respectively. This is an easy, fast and feasible method for monitoring the quality of raw pharmaceutical materials of MBZ according to polymorph purity.

The complete nucleotide sequence and genomic organization of Citrus Leprosis associated Virus, Cytoplasmatic type (CiLV-C).

The Citrus leprosis disease (CiL) is associated to a virus (CiLV) transmitted by Brevipalpus spp. mites (Acari: Tenuipalpidae). CiL is endemic in Brazil and its recently spreading to Central America represents a threat to citrus industry in the USA. Electron microscopy images show two forms of CiLV: a rare nuclear form, characterized by rod-shaped naked particle (CiLV-N) and a common cytoplasmic form (CiLV-C) associated with bacilliform-enveloped particle and cytoplasmic viroplasm. Due to this morphological feature, CiLV-C has been treated as Rhabdovirus-like. In this paper we present the complete nucleotide sequence and genomic organization of CiLV-C. It is a bipartite virus with sequence similarity to ssRNA positive plant virus. RNA1 encodes a putative replicase polyprotein and an ORF with no known function. RNA2 encodes 4 ORFs. pl5, p24 and p61 have no significant similarity to any known proteins and p32 encodes a protein with similarity to a viral movement protein. The CiLV-C sequences are associated with typical symptoms of CiL by RT-PCR. Phylogenetic analysis suggests that CiLV-C is probably a member of a new family of plant virus evolutionarily related to Tobamovirus.

Identification and genomic characterization of a new virus (Tymoviridae family) associated with citrus sudden death disease.

Citrus sudden death (CSD) is a new disease that has killed approximately 1 million orange trees in Brazil. Here we report the identification of a new virus associated with the disease. RNAs isolated from CSD-affected and nonaffected trees were used to construct cDNA libraries. A set of viral sequences present exclusively in libraries of CSD-affected trees was used to obtain the complete genome sequence of the new virus. Phylogenetic analysis revealed that this virus is a new member of the genus Marafivirus. Antibodies raised against the putative viral coat proteins allowed detection of viral antigens of expected sizes in affected plants. Electron microscopy of purified virus confirmed the presence of typical isometric Marafivirus particles. The screening of 773 affected and nonaffected citrus trees for the presence of the virus showed a 99.7% correlation between disease symptoms and the presence of the virus. We also detected the virus in aphids feeding on affected trees. These results suggest that this virus is likely to be the causative agent of CSD. The virus was named Citrus sudden death-associated virus.