The origin of the stereoselectivity in the asymmetric Michael reaction using chiral imines/secondary enamines under neutral conditions: a computational investigation

The diastereoselectivity in the asymmetric Michael reaction using chiral imines/secondary enamines under neutral conditions has been investigated with the help of AM1 calculations. The energetic differences between the two competing transition states involving enamino ketones 7d, 7g and methyl acrylate are in good agreement with the stereoselectivities observed with the corresponding chiral imines, derived from 1-phenylethylamine (de 95%) and from 1-cyclohexylethylamine (de 45%). The calculated transition structures indicate that steric factors govern the π-facial discrimination.     

Well‐defined PE‐b‐PDMS diblock copolymers via the combination of thiol‐ene click and esterification reactions: Facile synthesis and compatibilization for HDPE/silicone oil blends

Well‐defined diblock copolymers of linear polyethylene (PE) and poly(dimethylsiloxane) (PDMS) have been synthesized through a facile route combining the thiol‐ene click chemistry of vinyl‐terminated polyethylene (PE‐ene) and the sequential esterification reaction. The resulting diblock copolymers are characterized by ¹H NMR, FT‐IR, DSC, TGA, and TEM. In addition, the PE‐b‐PDMS diblock copolymers have been evaluated as compatibilizers in the blends of high‐density polyethylene (HDPE) and silicone oil. The morphological analysis and mechanical properties demonstrate that the compatibilized blends with low loading concentration of PE‐b‐PDMS display significant improvements in modulus of elasticity and elongation at break as compared to the uncompatibilized binary blends. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3205–3212     

Reaction between triphenylphosphine and aromatic amines in the presence of diethyl azodicarboxylate: an efficient synthesis of aryliminophosphoranes under neutral and mild conditions

An efficient synthesis of aryliminophosphoranes is described. A mixture of an aromatic amine, diethyl azodicarboxylate and triphenylphosphine undergo a Mitsonobu type reaction at ambient temperature in dry dichloromethane to afford aryliminophosphoranes in excellent yields.     

One-pot synthesis of dihydropyrimidones using silica-supported heteropoly acid as an efficient and reusable catalyst: Improved protocol conditions for the Biginelli reaction

An efficient synthesis of 3,4-dihydropyrimidinones or thiones (DHPMs) is described, using silica-supported heteropoly acid H₃PW₁₂O₄₀/SiO₂ (PW/SiO₂) for the first time as the catalyst from an aldehyde, β-keto ester and urea or thiourea in acetonitrile. Compared to the classical Biginelli reaction conditions, this method consistently has the advantage of excellent yields, mild reaction conditions, ease of workup, survival of different functional groups, and short reaction times.     

Nanomagnetically modified sulfuric acid (γ-Fe2O3@SiO2-OSO3H): an efficient, fast, and reusable green catalyst for the Ugi-like Groebke-Blackburn-Bienaymé three-component reaction under solvent-free conditions

Superparamagnetic nanoparticles of modified sulfuric acid (γ-Fe₂O₃@SiO₂-OSO₃H) represent a straightforward and green catalyst for the rapid synthesis of aminoimidazopyridine skeletons via the Ugi-like Groebke-Blackburn-Bienaymé three-component reaction. The γ-Fe₂O₃@SiO₂-OSO₃H catalyst could be recovered and reused in five reaction cycles, giving a total TON = 453. The products were prepared under solvent-free conditions without any additives.     

Competitive and selective Csp3-Br versus Csp2-Br bond activation in palladium-catalysed Suzuki cross-coupling: an experimental and theoretical study of the role of phosphine ligands

Phosphine ligands have been demonstrated to have an effect on reactivity and selectivity in the competitive intramolecular palladium-catalysed Suzuki-Miyaura coupling of dibromo sulfoxide 1a possessing two different hybridised electrophilic carbons. It was found that the bromine bond to the sp(3)-hybridised carbon is selectively replaced in the presence of unhindered phosphines such as PPh(3) or xantphos. The use of hindered phosphine ligands such as P(o-tol)(3) and P(1-naphthyl)(3) reversed the selectivity, conducting the cross-coupling at the Csp(2)-Br. Identical trends were observed in external competition experiments carried out with bromomethyl sulfoxide and different substituted bromoarenes. DFT and DFT/MM calculations showed that the selectivity observed is mainly due to the different facility of the ligands to dissociate. Bisphosphine catalysts favour coupling at the sp(3) carbon, whereas monophosphine catalysts prefer the sp(2) carbon.     

Indium(III) iodide-mediated Strecker reaction in water: an efficient and environmentally friendly approach for the synthesis of α-aminonitrile via a three-component condensation

A mild, efficient and environmentally friendly method has been developed for the synthesis of α-aminonitriles via a three-component condensation of aldehyde, amine and TMSCN in the presence of a catalytic amount of indium(III) iodide in water. The reactions proceeded smoothly at room temperature in water to generate the corresponding products in moderate to excellent yields.     

A novel four-component reaction of diethylamine, an aromatic aldehyde and an alkyl isocyanide with dialkyl acetylenedicarboxylates in the presence of silica gel: an efficient route for the regio- and stereoselective synthesis of sterically congested alkenes

The 1:1 intermediate generated by the addition of an isocyanide to a dialkyl acetylenedicarboxylate is trapped by the iminium ion intermediate that forms from the reaction between an aromatic aldehyde and diethylamine. The reactions were completed in the presence of silica gel powder. The product dialkyl 2-[(alkylamino)carbonyl]-3-[(Z)-1-(diethylamino)-1-arylmethylidene]succinates, were produced in acceptable yields. The reactions are completely regio- and stereoselective.     

Asymmetric Henry reaction catalysed by L‐proline derivatives in the presence of Cu(OAc)2: isolation and characterization of an in situ formed Cu(II) complex

Synthesis of asymmetric β‐nitroalcohols by the Henry reaction is one of the most exploited carbon–carbon bond‐forming reactions owing to the versatility of both functional groups for synthetic manipulation by functional group interconversion. Here we report synthesis of a series of proline‐derived compounds to study their catalytic activities for asymmetric Henry reaction in the presence of Cu(OAc)₂.H₂O. The proline derivative, 2‐((E)‐(((S)‐1‐benzylpyrrolidinyl)diphenylmethylimino)methyl)phenol 1 showed optimum catalytic activity. The catalytic species Cu(II)–1 complex, formed in situ, was isolated and characterized by various spectroscopic techniques and X‐ray crystallography to show a cis‐N₂O₂ coordination geometry. Asymmetric β‐nitroalcohols were achieved without the use of added base, unlike most of the reported protocols. Copyright © 2014 John Wiley & Sons, Ltd.     

Accurate reaction barrier heights of pericyclic reactions: Surprisingly large deviations for the CBS‐QB3 composite method and their consequences in DFT benchmark studies

Accurate barrier heights are obtained for the 26 pericyclic reactions in the BHPERI dataset by means of the high‐level Wn‐F12 thermochemical protocols. Very often, the complete basis set (CBS)‐type composite methods are used in similar situations, but herein it is shown that they in fact result in surprisingly large errors with root mean square deviations (RMSDs) of about 2.5 kcal mol^?1. In comparison, other composite methods, particularly G4‐type and estimated coupled cluster with singles, doubles, and quasiperturbative triple excitations [CCSD(T)/CBS] approaches, show deviations well below the chemical‐accuracy threshold of 1 kcal mol^?1. With the exception of SCS‐MP2 and the herein newly introduced MP3.5 approach, all other tested Møller‐Plesset perturbative procedures give poor performance with RMSDs of up to 8.0 kcal mol^?1. The finding that CBS‐type methods fail for barrier heights of these reactions is unexpected and it is particularly troublesome given that they are often used to obtain reference values for benchmark studies. Significant differences are identified in the interpretation and final ranking of density functional theory (DFT) methods when using the original CBS‐QB3 rather than the new Wn‐F12 reference values for BHPERI. In particular, it is observed that the more accurate Wn‐F12 benchmark results in lower statistical errors for those methods that are generally considered to be robust and accurate. Two examples are the PW6B95‐D3(BJ) hybrid‐meta‐general‐gradient approximation and the PWPB95‐D3(BJ) double‐hybrid functionals, which result in the lowest RMSDs of the entire DFT study (1.3 and 1.0 kcal mol^?1, respectively). These results indicate that CBS‐QB3 should be applied with caution in computational modeling and benchmark studies involving related systems. © 2015 Wiley Periodicals, Inc.     

Convergence in the QM‐only and QM/MM modeling of enzymatic reactions: A case study for acetylene hydratase

We report systematic quantum mechanics‐only (QM‐only) and QM/molecular mechanics (MM) calculations on an enzyme‐catalyzed reaction to assess the convergence behavior of QM‐only and QM/MM energies with respect to the size of the chosen QM region. The QM and MM parts are described by density functional theory (typically B3LYP/def2‐SVP) and the CHARMM force field, respectively. Extending our previous work on acetylene hydratase with QM regions up to 157 atoms (Liao and Thiel, J. Chem. Theory Comput. 2012, 8, 3793), we performed QM/MM geometry optimizations with a QM region M4 composed of 408 atoms, as well as further QM/MM single‐point calculations with even larger QM regions up to 657 atoms. A charge deletion analysis was conducted for the previously used QM/MM model ( M3a , with a QM region of 157 atoms) to identify all MM residues with strong electrostatic contributions to the reaction energetics (typically more than 2 kcal/mol), which were then included in M4 . QM/MM calculations with this large QM region M4 lead to the same overall mechanism as the previous QM/MM calculations with M3a , but there are some variations in the relative energies of the stationary points, with a mean absolute deviation (MAD) of 2.7 kcal/mol. The energies of the two relevant transition states are close to each other at all levels applied (typically within 2 kcal/mol), with the first (second) one being rate‐limiting in the QM/MM calculations with M3a ( M4 ). QM‐only gas‐phase calculations give a very similar energy profile for QM region M4 (MAD of 1.7 kcal/mol), contrary to the situation for M3a where we had previously found significant discrepancies between the QM‐only and QM/MM results (MAD of 7.9 kcal/mol). Extension of the QM region beyond M4 up to M7 (657 atoms) leads to only rather small variations in the relative energies from single‐point QM‐only and QM/MM calculations (MAD typically about 1–2 kcal/mol). In the case of acetylene hydratase, a model with 408 QM atoms thus seems sufficient to achieve convergence in the computed relative energies to within 1–2 kcal/mol.Copyright © 2013 Wiley Periodicals, Inc.     

On the mechanisms of degenerate ligand exchange in [M(CH(3))](+)/CH(4) Couples (M=Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, Pt) as explored by mass spectrometric and computational studies: oxidative addition/reductive elimination versus sigma-complex-assisted metathesis

The degenerate ligand exchange in [M(CH(3))](+)/CH(4) couples occurs in the gas phase at room temperature for M=Ni, Ru, Rh, Pd, and Pt, whereas the complexes containing Fe and Co are unreactive. Details of hydrogen-atom scrambling versus direct ligand switch have been uncovered by labeling experiments with CD(4) and (13)CH(4), respectively. The reactivity scale ranges from unreactive (M=Fe, Co) or inefficient (M=Ni, Pd) to moderately (M=Ru) and rather reactive (M=Rh, Pt). Quite extensive, but not complete, H/D exchange between the hydrogen atoms of the incoming and outgoing methyl groups is observed for M=Pt, whereas for M=Ni and Pd a predominantly direct ligand switch prevails. DFT calculations performed at the B3LYP level of theory account well for the thermal nonreactivity of the Fe and Co couples. For [Ni[CH(3))](+)/CH(4), a sigma-complex-assisted metathesis (sigma-CAM) is operative such that, in a two-state reactivity (TSR) scenario, two spin flips between the (3)A ground and (1)A excited states take place at the entrance and exit channels of the encounter complexes. For M=Ru and Rh, only oxidative addition/reductive elimination (OA/RE) is favored energetically, and the reaction is confined to the electronic ground states (3)A and (2)A. In contrast, for the [Pd(CH(3))](+)/CH(4) system, on the (1)A ground-state potential-energy surface both the OA/RE and sigma-CAM variants are energetically comparable, and the small reaction efficiency for the ligand switch is reflected in transition states located energetically close to the reactants. For the [M(CH(3))](+)/CH(4) complexes of the 5d elements, the sigma-CAM mechanism does not play a role. For M=Pt, the energetically most favored path proceeds in a spin-conserving manner on the (1)A potential-energy surface, which accounts for the extensive single and double hydrogen-atom exchange preceding ligand exchange. Although for M=Os and Ir the [M(CH(3))](+) complexes could not be generated experimentally, computational studies predict that both systems may undergo thermal reaction with CH(4), and an OA/RE mechanism will commence on the respective high-spin ground states; however, the bond-activation and ligand-exchange steps will occur on the excited low-spin surfaces in a TSR scenario.     

Influence of hydrogen bonding in the activation of nucleophiles: PhSH-(catalytic) KF in N-methyl-2-pyrrolidone as an efficient protocol for selective cleavage of alkyl/aryl esters and aryl alkyl ethers under nonhydrolytic and neutral conditions

The nucleophilicity of arenethiols can be augmented via hydrogen bonding with "naked" halide anion. The activity of the halide anions follow the order F(-) > Cl(-) approximately Br(-) approximately I(-) and is dependent on the countercation (Bu(4)N approximately Cs approximately K > Na > Li). The solvent plays an important role in nucleophilic activation as well as regeneration of the effective nucleophile (e.g. ArS(-)) and those with high dielectric constant, high molecular polarizability, high donor number (DN), and low acceptor number (AN) are the most effective. Selective deprotection of alkyl/aryl esters and aryl alkyl ethers can be achieved under nonhydrolytic and neutral conditions by the treatment with thiophenol in 1-methyl-2-pyrrolidone (NMP) in the presence of a catalytic amount of KF. Aryl esters are selectively deprotected in the presence of alkyl esters and alkyl methyl ethers during intramolecular competitions.     

A novel three-component reaction of a secondary amine and a 2-hydroxybenzaldehyde derivative with an isocyanide in the presence of silica gel: an efficient one-pot synthesis of benzo[b]furan derivatives

Reaction of an isocyanide with an iminium ion intermediate, formed by reaction between an electron-poor 2-hydroxybenzaldehyde derivative and a secondary amine in the presence of silica gel proceeds smoothly at room temperature to afford benzo[b]furan derivatives in high yields.     

Development and validation of an UPLC‐Q/TOF‐MS assay for the quantitation of neopanaxadiol in beagle dog plasma: Application to a pharmacokinetic study

Neopanaxadiol (NPD), the main panaxadiol constituent of Panax ginseng C. A. Meyer (Araliaceae), has been regarded as the active component for the treatment of Alzheimer's disease. However, few references are available about pharmacokinetic evaluation for NPD. Accordingly, a rapid and sensitive method for quantitative analysis of NPD in beagle dog plasma based on ultra‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry was developed and validated. Analytes were extracted from plasma by liquid–liquid extraction and chromatographic separation was achieved on an Agilent Zorbax Stable Bond C₁₈ column. Detection was performed in the positive ion mode using multiple reaction monitoring of the transitions both at m/z 461.4 → 425.4 for NPD and internal standard of panaxadiol. All validation parameters, such as lower limit of quantitation, linearity, specificity, precision, accuracy, extraction recovery, matrix effect and stability, were within acceptable ranges and the method was appropriate for multitude sample determination. After oral intake, NPD was slowly absorbed and eliminated from circulatory blood system and corresponding plasma exposure was low. Application of this quantitative method will yield the first pharmacokinetic profile after oral administration of NPD to beagle dog. The information obtained here will be useful to understand the pharmacological effects of NPD.     

Oxidative addition of 1,4‐dichloro‐2‐butyne to an organoplatinum complex: A new precursor for synthesis of ultrasmall Pt nanoparticles thin film at liquid/liquid interface as the electrocatalyst in methanol oxidation reaction

In this study, the usage of ClCH₂CCCH₂Cl alkyne as a reagent for the oxidative addition reaction with organoplatinum?(II) complex [PtMe₂(bipy)] ( 1 ), in which bipy = 2,2′‐bipyridine to give a mixture including of trans‐[PtClMe₂(CH₂CCCH₂Cl)(bipy)] ( 2a ) and a cis‐[PtClMe₂(CH₂CCCH₂Cl)(bipy)] ( 2b ) complexes is reported. Kinetic study was investigated by monitoring the disappearance of the metal‐to‐ligand charge transfer (MLCT) band in the UV–Vis spectra. ¹H NMR experimental results confirmed that trans isomer ( 2a ) is more stable than its corresponding cis isomer. A liquid–liquid planar interface has been employed as a template for self‐assembly of platinum nanoparticles. The as prepared complex was applied for the synthesis of platinum thin film that characterized by transmission electron microscopy (TEM), X‐ray diffraction (XRD), energy dispersive analysis of X‐rays (EDAX), field emission‐scanning electron micrographs (FE‐SEM) and elemental mapping. The electrocatalytical activity of Pt thin film was investigated in methanol oxidation reaction.     

Fit-for-purpose in veterinary drug residue analysis: development and validation of an LC-MS/MS method for the screening of thirty illicit drugs in bovine urine

A selective and sensitive method for screening 31 analytes (nine corticosteroids, eight β‐agonists, seven anabolic steroids, six promazines and zeranol) in bovine urine was validated according to 2002/657/EC guidelines. Upon optimization of sample treatment conditions, the extraction was performed by diethylether at pH 9, after deconjugation. Extraction yields (R%) proved higher than 70% for 19 analytes, 50<R%<70 for 5 analytes, lower than 50% but reproducible for the remaining six analytes. The analyses were carried out using HPLC‐ESI‐MS/MS. The method sensitivity proved high enough to largely exceed the CCβ requirements of the Italian residue detection plan, ranging from 1 to 3 ng/mL (20 ng/mL for promazines). The present method allowed the simultaneous analysis of most drugs for which the European legislation prescribes official controls. Its practical applicability was verified on 494 real samples as an alternative to the traditional screening protocols based on multiple immunometric analysis, demonstrating high efficiency and comprehensive investigation capacity, allowing epidemiological assessment of the current trends in cattle breeding drug abuse. Among non‐compliant results, nine borderline cases of growth‐promoters illegal treatments, making use of long‐term low‐dosage administrations and typically yielding urine residues below the cut‐off value for immunochemical methods, were detected by using the present LC‐MS/MS method.     

Development and validation of an LC‐MS/MS method for the determination of bullatine A in rat plasma: application to a pharmacokinetic study

Bullatine A is a diterpenoid alkaloid of Xue‐Shang‐Yi‐Zhi‐Hao (Aconitum brachypodum), which is widely used in traditional Chinese medicine for the treatment of rheumatism and pain. The plasma levels of bullatine A were measured by a rapid and sensitive LC‐MS/MS method. Samples were prepared using acetonitrile precipitation and the separation of bullatine A was achieved on a Capcell Pak MG‐C₁₈ column by isocratic elution using acetonitrile (phase A) and 0.1% formic acid (phase B, pH 4.0; A:B, 30:70, v/v) as the mobile phase at a flow rate of 0.5 mL/min. Detection was performed on a triple‐quadrupole tandem mass spectrometer by multiple‐reaction monitoring of the transitions at m/z 344.2 → 105.2 for bullatine A and m/z 256.2 → 167.1 for the internal standard. The linearity was found to be within the concentration range of 1.32–440 ng/mL with a lower limit of quantification of 1.32 ng/mL. Only 1.3 min was needed for an each analytical run. This method was successfully applied in the determination of the active component bullatine A in rat plasma after intramuscular administration of A. brachypodum injection. Copyright © 2015 John Wiley & Sons, Ltd.