Microwave promoted amination of 3-bromoisoxazoles

This Letter describes the amination of 3-bromoisoxazoles by a nucleophilic aromatic substitution reaction. We have found 3-bromoisoxazoles to be inert to substitution under thermal conditions, however, the employment of phosphazene bases under microwave irradiation facilitates the amination process and allows the corresponding 3-aminoisoxazoles to be isolated in moderate yield.     

Vibrational Stark Effects on Carbonyl, Nitrile, and Nitrosyl Compounds Including Heme Ligands, CO, CN, and NO, Studied with Density Functional Theory

Changes in the matrix electric field in a protein, due for example to mutations or structural fluctuations, can be correlated with changes in the vibrational transition frequencies of suitable chromophores measured by IR spectroscopy through the Stark tuning rate. To make this correlation, the Stark tuning rate must be known from experiment or theory. In this paper, density functional theory at the B3LYP/TZV level of theory is used to compute the Stark tuning rate of adducts of heme porphyrin, namely, -CO, -CN, and -NO+ compounds. The results are compared with the corresponding vibrational frequencies-field dependencies from vibrational Stark spectroscopy of heme-proteins. The zero-field computed Stark tuning rate of 1.3 cm-1/MV/cm for heme-CO is in agreement with experiment, where typically the rate is 2.4/f cm-1/MV/cm for myoglobin, where f is a local field correction between 1.1 and 1.4. Several small nitrile, carbonyl, and dinitrile molecules were studied to rationalize the findings for the heme-adducted models. Here, the higher B3LYP/6-311++G(2d,2p) level of theory could be used so the agreement with recent experimental results is even better than for heme-adducted groups.     

Time evolution studies of the H2O/quartz interface using sum frequency generation, atomic force microscopy, and molecular dynamics

Many interfacial studies on solid surfaces, for example, quartz/water, assume that a standard cleaning procedure regenerates the surface reproducibly. In the reported work, the results of two surface specific techniques, sum frequency generation (SFG) spectroscopy and atomic force microscopy, show that the effects of prolonged exposure to Nanopure water and to pH 10 NaOH are distinctly different. In conjunction with the experimental data, molecular mechanics is used to correlate the SFG spectral frequencies to the hydrogen stretching vibrations of the surface-bound water molecules. It is found that after 17 days of soaking in water, water molecules penetrate into the SiO2 matrix to produce a swollen and amorphous layer; it is likely that broken Si-O bonds from the polishing process serve as nucleation sites for hydration and swelling. Disorder introduced in the interfacial water layer is detected by the rising intensity of the weakly hydrogen-bonded SFG peak at 3450 cm(-1). Dominance of the 3450 cm(-1) is absent in a pH 10, NaOH-soaked quartz disk, indicating that the strong hydrogen-bonded network in water remains intact.     

Squeezing the [Cu-OH...H2O-Cu]3+ bridge by cryptate encapsulation

Treatment of cryptand L(1) with Cu(II) generates a H3O2(-)-bridged dicopper(II) cryptate, 2, where the guest anion has responded to steric constraint by a significant shortening of the O-O distance to 2.325(9) A; computational optimization at the B3LYP/6-31(d) level suggests that the bridging O-H...O H-bond is bent (approximately 157 degrees) but that the barrier to interchange of the bridging H atom is low (<4 kJ mol(-1)). This cryptate, rather than the [Cu2L(1)muCN]3+ species recently claimed to derive from cleavage of the C-C bond of the solvent, is the product of acetonitrile recrystallization of the initially formed reaction product, 1.     

Data-Independent Microbial Metabolomics with Ambient Ionization Mass Spectrometry

Atmospheric ionization methods are ideally suited for prolonged MS/MS analysis. Data-independent MS/MS is a complementary technique for analysis of biological samples as compared to data-dependent analysis. Here, we pair data-independent MS/MS with the ambient ionization method nanospray desorption electrospray ionization (nanoDESI) for untargeted analysis of bacterial metabolites. Proof-of-principle data and analysis are illustrated by sampling Bacillus subtilis and Pseudomonas aeruginosa directly from Petri dishes. We found that this technique enables facile comparisons between strains via MS and MS/MS plots which can be translated to chemically informative molecular maps through MS/MS networking. The development of novel techniques to characterize microbial metabolites allows rapid and efficient analysis of metabolic exchange factors. This is motivated by our desire to develop novel techniques to explore the role of interspecies interactions in the environment, health, and disease. This is a contribution to honor Professor Catherine C. Fenselau in receiving the prestigious ASMS Award for a Distinguished Contribution in Mass Spectrometry for her pioneering work on microbial mass spectrometry.

Gold(I)-catalyzed diastereo- and enantioselective 1,3-dipolar cycloaddition and Mannich reactions of azlactones

Azlactones participate in stereoselective reactions with electron-deficient alkenes and N-sulfonyl aldimines to give products of 1,3-dipolar cycloaddition and Mannich addition reactions, respectively. Both of these reactions proceed with good to excellent diastereo- and enantioselectivity using a single class of gold catalysts, namely C(2)-symmetric bis(phosphinegold(I) carboxylate) complexes. The development of the azlactone Mannich reaction to provide fully protected anti-α,β-diamino acid derivatives is described. 1,3-Dipolar cycloaddition reactions of several acyclic 1,2-disubstituted alkenes and the chemistry of the resultant cycloadducts are examined to probe the stereochemical course of this reaction. Reaction kinetics and tandem mass spectrometry studies of both the cycloaddition and Mannich reactions are reported. These studies support a mechanism in which the gold complexes catalyze addition reactions through nucleophile activation rather than the more typical activation of the electrophilic reaction component.     

Global QSAR models of skin sensitisers for regulatory purposes

Background

The new European Regulation on chemical safety, REACH, (Registration, Evaluation, Authorisation and Restriction of CHemical substances), is in the process of being implemented. Many chemicals used in industry require additional testing to comply with the REACH regulations. At the same time EU member states are attempting to reduce the number of animals used in experiments under the 3 Rs policy, (refining, reducing, and replacing the use of animals in laboratory procedures). Computational techniques such as QSAR have the potential to offer an alternative for generating REACH data. The FP6 project CAESAR was aimed at developing QSAR models for 5 key toxicological endpoints of which skin sensitisation was one.

Results

This paper reports the development of two global QSAR models using two different computational approaches, which contribute to the hybrid model freely available online.

Conclusions

The QSAR models for assessing skin sensitisation have been developed and tested under stringent quality criteria to fulfil the principles laid down by the OECD. The final models, accessible from CAESAR website, offer a robust and reliable method of assessing skin sensitisation for regulatory use.

     

C-H bond functionalization in the synthesis of fused 1,2,3-triazoles

A highly modular approach to fused 1,2,3-triazoles has been developed featuring a one-pot procedure combining copper(I) catalyzed azide-alkyne cycloaddition and palladium-catalyzed C-H bond functionalization. A class of structurally unique heterocycles was synthesized in good yields.     

Rapid determination of aristolochic acids I and II in herbal products and biological samples by ultra-high-pressure liquid chromatography-tandem mass spectrometry

Aristolochic acids (AAs) are a mixture of structural-related compounds, in which aristolochic acid I (AA I) and aristolochic acid II (AA II) are reported to be correlated with Aristolochic acid nephropathy (AAN). In this work, a rapid and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to determine AA I and AA II in herbal products and biological fluids. By using gradient elution with a mobile phase composed of a mixture of 10 mM ammonium formate buffer (pH 3.0) and acetonitrile, AAs could be determined within 10 min. Under optimum UHPLC-MS/MS conditions, the limit of detections was 0.14 and 0.26 ng mL⁻¹ for AA I and AA II, respectively. Run-to-run repeatability and intermediate precision of peak area for AA I and AA II were less than 5.74% relative standard deviation (RSD). Accuracy was tested by spiking 10, 100 and 1000 ng mL⁻¹ in rat serum and the recoveries were within 76.5-92.9%. Matrix effects were within 78.8-127.7%. The developed method was successfully applied to determine AA I and AA II in several herbal products and to investigate their pharmacokinetic behavior in female Wister rats. The result shows that the developed UHPLC-MS/MS method is efficient, sensitive, and accurate for the determination of AA I and AA II in herbal products and biological samples.     

Enhanced detonation sensitivities of silicon analogs of PETN: reaction force analysis and the role of σ–hole interactions

Si-pentaerythritol tetranitrate (PETN), Si[CH₂ONO₂]₄, is a silicon analog of the widely used explosive PETN, C[CH₂ONO₂]₄. Si-PETN is extremely sensitive to impact, much more so than PETN. This was attributed by Liu et al. to Si-PETN having a much lower activation barrier to decomposition, via a facile rearrangement that is not as readily available to PETN, and which releases considerable energy that can promote further steps. We have investigated computationally why the barrier to the rearrangement is so much lower for Si-PETN than for PETN, using 5, (H₃C)₃C–CH₂ONO₂, and 6, (H₃C)₃Si–CH₂ONO₂, as models for PETN and Si-PETN. Reaction force analysis shows that most of the difference between the rearrangement barriers for 5 and 6 comes about in the initial (reactant) stages of the processes, in which 6 benefits from a 1,3 electrostatic interaction involving a positive σ–hole on the silicon and the negative linking oxygen. The analogous interaction is weaker in 5, since the central carbon does not have positive σ–holes; furthermore, this carbon is less able than silicon to temporarily expand its coordination sphere. A similar explanation involving a positive silicon σ–hole and a linking oxygen is proposed for Si-PETN. The greater exothermicity of the rearrangement of 6 (and also Si-PETN) can be rationalized, following Liu et al., in terms of the formation of the strong Si–O bond.