Mechanistic Views on First-row Earth-Abundant Transition Metal Catalyzed Ullmann-type O-Arylation Reactions.

Transition metal-catalyzed reactions have attracted much attention in synthetic organic chemistry due to their important role in the formation of C-heteroatom bonds. Ullmann coupling has risen in prominence in recent decades owing to its utilization in the synthesis of biaryl ethers found in a wide range of natural products together with biologically essential molecules, including antibiotics and major industrial polymers. In this article we provide the current understanding of the theoretical aspects of the underlying mechanism of the Ullmann-type O-arylation reaction.

A detailed theoretical investigation to unravel the molecular mechanism of the ligand-free copper-catalyzed Suzuki cross-coupling reaction.

The Suzuki-Miyaura coupling (SMC) represents a very efficacious method for constructing C-C bonds in organic synthesis. The ligand-free variants of SMC have been grabbing attention these days. Despite this momentousness, the mechanistic details of the ligand-free variants are scant in the literature. Herein, we have carried out a detailed mechanistic investigation into the ligand-free Cu-catalyzed SMC of unsaturated organic halides with aryl boronic acid with the aid of density functional theory (DFT) calculations employing the conductor-like polarizable continuum model (CPCM) method. The present study elucidates that in the absence of ancillary ligands on the metal, the substrates, base, and solvent molecules could act as pseudo-ancillary ligands to facilitate the cross-coupling reaction. The investigation further revealed that unsaturated halides like alkynyl halides/vinyl halides could act as good ancillary ligands for copper by forming a Cu-π intermediate and promoting a facile transmetalation process. However, regarding the oxidative addition and reductive elimination steps, a concerted pathway is observed contrary to Pd catalyzed Suzuki coupling, owing to the instability of Cu(III) species and the favourability of Csp2-Csp bond formation. In the whole set of mechanisms explored, oxidative addition/oxidative nucleophilic substitution was the rate-determining step in all the cases. A thermodynamically stable π-coordinated intermediate species where the substrate and base molecule are coordinated to the metal center is identified as the rate-determining species for the ligand-free Suzuki cross-coupling reaction. The presence of the aforesaid intermediate increases the energy span and consequently the activation barrier for the rate-determining step. This study unveiled a theoretical rationale for the high-temperature requirement in the ligand-free Cu-catalyzed SMC reaction.

LC-MS analysis of p-aminosalicylic acid under electrospray ionization conditions manifests a profound solvent effect.

Selected-ion recording (SIR) or multiple-reaction monitoring (MRM) protocols are widely employed for the quantification of targeted analytes by liquid chromatography-mass spectrometry (LC-MS). After chromatographic separation, analytes are desolvated and converted to gaseous ions usually by electrospray-ionization. The chromatographic peaks generated in this way are then integrated for quantification. It is generally assumed that the chromatographic peak intensities are dependent only on the selected MRM-transition protocols and the instrumental parameters set on the mass spectrometer. Using p-aminosalicylic acid (PAS) as a model compound, we demonstrate that the nature of the LC mobile phase exerts a significant effect on the chromatographic peak intensities. Under identical mass spectrometric conditions, chromatographic peak intensities recorded with methanol as the mobile phase were drastically different from those acquired using acetonitrile as the eluent. In fact, the product-ion mass spectra recorded with protonated PAS under different solvent conditions were qualitatively different. The observed differences were attributed to the existence of different protomers of PAS in the gas phase in dissimilar ratios under different solvent-spray conditions. Results from ion-mobility mass spectrometry experiments confirmed this hypothesis. For example, when PAS was sprayed from an acetonitrile solution, the arrival-time profile recorded from the mass-selected m/z 154 ion for protonated PAS showed essentially one arrival-time peak for the N-protonated tautomer. In contrast, the profile recorded from a methanolic PAS solution showed a different arrival-time peak for a more mobile protomer, which was recognized as the carbonyl-protonated PAS. The coexistence of protomers in different and variable ratios in an ensemble of ions generated by electrospray ionization of a single pure compound wields strong ramifications on the identification and quantification of analytes by LC-MS. However, the inclusion of an ion-mobility separator before the mass-selected ions are fragmented and detected by mass spectrometry ameliorates the complications rendered by the coexistence of different protomers and deprotomers.

Cerebral outcomes in a preterm baboon model of early versus delayed nasal continuous positive airway pressure.

BACKGROUND: The survival of prematurely born infants has greatly increased in recent decades because of advances in neonatal intensive care, which have included the advent of ventilatory therapies. However, there is limited knowledge as to the impact of these therapies on the developing brain. The purpose of this work was to evaluate the influence of randomized respiratory therapy with either early continuous positive airway pressure or delayed continuous positive airway pressure preceded by positive pressure ventilation on the extent of brain injury and altered development in a prematurely delivered primate model. METHODS: Fetal baboons were delivered at 125 days of gestation (term: approximately 185 days of gestation) by cesarean section. Animals were maintained for 28 days postdelivery with either: early continuous positive airway pressure (commencing at 24 hours; n = 6) or delayed continuous positive airway pressure (positive pressure ventilation for 5 days followed by nCPAP; n = 5). Gestational controls (n = 4) were delivered at 153 days of gestation. At the completion of the study, animals were killed, the brains were assessed histologically for growth and development, and evidence of cerebral injury and indices for both parameters were formulated. RESULTS: Brain and body weights were reduced in all of the nasal continuous positive airway pressure animals compared with controls; however, the brain/body weight ratio was increased in early continuous positive airway pressure animals. Within both nasal continuous positive airway pressure groups compared with controls, there was increased gliosis in the subcortical and deep white matter and cortex and a persistence of radial glia. Early continuous positive airway pressure was associated with less cerebral injury than delayed continuous positive airway pressure therapy. Neuropathologies were not observed in controls. CONCLUSIONS: Premature delivery, in the absence of potentiating factors, such as hypoxia or infection, is associated with a decrease in brain growth and the presence of subtle brain injury, which seems to be modified by respiratory therapies with early continuous positive airway pressure being associated with less overall cerebral injury.