Microwave-assisted tandem Wittig-intramolecular Diels-Alder cycloaddition. Product distribution and stereochemical assignment

The IMDA cycloadditions of 10 different ester-tethered 1,3,8-nonatrienes have been examined under controlled microwave heating (MeCN, 180 °C, 30 min), giving 90-99% yields, and the stereochemical outcome of the exo and endo adducts established together with X-ray crystal structural analysis. A microwave-assisted tandem Wittig-IMDA cycloaddition protocol has been established for a modular synthesis of the bicyclic lactones starting from α-bromoacetates of 2,4-pentadien-1-ols and α-oxo carbonyl compounds in the presence of PPh₃ and 2,6-lutidine (MeCN, 180 °C, 30 min). The overall yields of the tandem reactions are 68-80% and the stereoselectivity of the major adducts formed from E-substituted 1,3,8-nonatriene is the same as that observed for the purified 1,3,8-nonatrienes.     

Biosynthesis and antioxidant activity of 4NRC β-glycoside

This Letter describes glycosylation of 4-Nerolidylcatechol (4-NRC) the major secondary metabolite from Pothomorphe peltata and Pothomorphe umbellata showing remarkable antioxidant, antimalarial, anti-inflammatory, and anti-HIV activities. One step biosynthesis was catalyzed by Cunninghamella echinulata ATCC 9245 and the reaction was undertaken in PDSM medium at 27 °C, 200 rpm for 96 h. After purification by silica gel flash column chromatography the 4-NRC β-glycoside was identified by ultrahigh resolution mass spectrometry and ¹H NMR. The antioxidant activity was evaluated by differential pulse voltammetry.     

An improved liquid chromatography–tandem mass spectrometry method for the quantification of 4-aminobiphenyl DNA adducts in urinary bladder cells and tissues

Exposure to 4-aminobiphenyl (4-ABP), an environmental and tobacco smoke carcinogen that targets the bladder urothelium, leads to DNA adduct formation and cancer development [1]. Two major analytical challenges in DNA adduct analysis of human samples have been limited sample availability and the need to reach detection limits approaching the part-per-billion threshold. By operating at nano-flow rates and incorporating a capillary analytical column in addition to an online sample enrichment step, we have developed a sensitive and quantitative HPLC–MS/MS method appropriate for the analysis of such samples. This assay for the deoxyguanosine adduct of 4-ABP (dG-C8-4-ABP) gave mass detection limits of 20 amol in 1.25 μg of DNA (5 adducts in 10⁹ nucleosides) with a linear range of 70 amol to 70 fmol. 4-ABP-exposed human bladder cells and rat bladder tissue were analyzed in triplicate, and higher dose concentrations led to increased numbers of detected adducts. It was subsequently established that sample requirements could be further reduced to 1 μg digestions and the equivalent of 250 ng DNA per injection for the detection of low levels of dG-C8-4-ABP in a matrix of exfoliated human urothelial cell DNA. This method is appropriate for the characterization and quantification of DNA adducts in human samples and can lead to a greater understanding of their role in carcinogenesis and also facilitate evaluation of chemopreventive agents.     

Synthesis of 2-ferrocenylidene-4-cyclopentene-1,3-diones

A squarate-based synthesis of 2-ferrocenylidene-4-cyclopentene-1,3-diones is described. When refluxed in dioxane at 100 °C, heated with silica gel as a solvent free grinded solid mixture at 125 °C or stirred with silica gel in ethyl acetate at room temperature, 4-ferrocenylethynyl-4-hydroxy-2-cyclobutenones, prepared from ethynylferrocene and 3-cyclobutene-1,2-diones, afforded 2-ferrocenylidene-4-cyclopentene-1,3-diones as the major or single product of the reaction. In some cases, ferrocenyl quinones also resulted from these reactions as the minor products. The major or exclusive formation of 2-ferrocenylidene-4-cyclopentene-1,3-diones is attributed to the radical-stabilizing ability of the ferrocenyl group.     

Synthesis, characterization and application of a novel mercapto- and amine-bifunctionalized silica for speciation/sorption of inorganic arsenic prior to inductively coupled plasma mass spectrometric determination

A bifunctional sorbent, (NH₂ + SH)silica, containing both amine and mercapto functionalities was prepared by modification of silica gel with 3-(triethoxysilyl)propylamine and (3-mercaptopropyl)trimethoxysilane. In addition to the bifunctional sorbent, silica gel was modified individually with the functional mercapto- and amino-silanes, and the mono-functional sorbents, namely (SH)silica and (NH₂)silica, were also mechanically mixed ((NH₂)silica + (SH)silica) for the sake of comparison of sorption performances. It has been demonstrated that (SH)silica shows quantitative sorption only to As(III) at two pH values, 1.0 and 9.0, while (NH₂)silica displays selectivity only towards As(V) at pH 3.0. On the other hand, the bifunctional (NH₂ + SH)silica possesses the efficient features of the two mono-functionalized sorbents; for example, it retains As(III) at a wider pH range, from 1.0 to at least 9.0 with the exception at pH 2.0, and it also shows quantitative sorption to As(V) at pH 3.0. This property gives the bifunctional (NH₂ + SH)silica a better flexibility in terms of sorption performance as a function of solution pH. The mechanically mixed (NH₂)silica + (SH)silica exhibits a similar but less efficient sorption behavior compared to the bifunctional sorbent. Desorption of both As(III) and As(V) species can be realized using 0.5 M NaOH. The validity of the proposed method was checked through the analysis of a standard reference material and a good correlation was obtained between the certified (26.67 μg L⁻¹) and determined (27.53 ± 0.37 μg L⁻¹) values. Spike recovery tests realized with ultrapure water (93.0 ± 2.3%) and drinking water (86.9 ± 1.2%) also confirmed the applicability of the method.     

Development of a derivatisation method for the analysis of aldehyde modified amino acid residues in proteins by Fourier transform mass spectrometry

A method was developed for the analysis of amino acids within bovine serum albumin (BSA) which had been modified by reaction with different enals. BSA was reacted with the aldehydes and the reaction products were stabilised by reaction with NaBH₄. The protein was then hydrolysed with 6N HCl and the hydrolysis products were analysed by liquid chromatography-mass spectrometry (LC-MS). The modified amino acids were derivatised with propylchloroformate. High resolution mass spectrometry carried out using an LTQ-Orbitrap instrument which was able to characterise a wide range of adducts. In addition double adducts were observed to be formed with 4-hydroxynonenal (HNE) and lysine or lysine + histidine. Qualitatively it was possible to consistently observe a pyridinium adduct formed between lysine and pentenal in human plasma from normal subjects.     

Intramolecular Diels-Alder reaction of α-fluoroacrylate derivatives promoted by novel bidentate aluminum Lewis acid

Intramolecular Diels-Alder (IMDA) reaction of α-fluoroacrylate derivatives 1a-e having 1,7,9-decatrienoate system is efficiently promoted by the novel bidentate Lewis acid A generated in situ by mixing 3,3′,5,5′-tetrabromo-1,1′-biphenyl-2,2′-diol (Br₄BIPOL, 1 mol) and trimethylaluminum (2 mol). The IMDA reaction of α-fluoroacrylates proceeds via endo-boat transition state as in the case of the corresponding non-fluorinated acrylate.     

Fast preparation of dihydrocyclocitral from citronellal under solventless microwave irradiation

Dihydrocyclocitral, a useful reagent in organic synthesis, has been synthesized in high yield and with high stereoselectivity from citronellal under microwave irradiation in two steps, involving acetic anhydride under base catalysis, then p-toluenesulfonic acid adsorbed on silica gel under solventless conditions (80% yield, reaction time 22 min).     

Isotope dilution-thermal ionisation mass spectrometric analysis for tin in a fly ash material

Isotope dilution-thermal ionisation mass spectrometry (ID-TIMS) analysis has been applied to the determination of tin in a fly ash sample supplied by the EC Joint Research Centre (Ispra, Italy). The proposed procedure includes the silica gel/phosphoric acid technique for tin thermal ionisation activation and a strict heating protocol for isotope ratio measurements. Instrumental mass discrimination factor has been previously determined measuring a natural tin standard solution. Spike solution has been prepared from ¹¹²Sn-enriched metal and quantified by reverse isotope dilution analysis. Two sample aliquots were spiked and tin was extracted with 4.5 M HCl during 25 min ultrasound exposure time. Due to the complex matrix of this fly ash material, a two-step purification stage using ion-exchange chromatography was required prior TIMS analysis. Obtained results for the two sample-spike blends (10.11 ± 0.55 and 10.50 ± 0.64 μmol g⁻¹) are comparable, both value and uncertainty. Also a good reproducibility is observed between measurements. The proposed ID-TIMS procedure, as a primary method and due to the lack of fly ash reference materials certified for tin content, can be used to validate more routine methodologies applied to tin determination in this kind of samples.     

Adduct formation in LC-ESI-MS of nonylphenol ethoxylates: mass spectrometrical, theoretical and quantitative analytical aspects

The analysis of nonylphenol ethoxylate (A₉PEO_n) surfactants with LC-ESI-MS was investigated in a detailed study of the formation of different types of adducts. Part of the observations was explained by calculating their relative stabilities using molecular dynamics techniques.Strong differences in adduct formation behaviour were found for different oligomers.Beside the common sodium adducts, surfactant dimer adducts [2 × A₉PEO_1,2 + Na]⁺, adducts including a solvent molecule [A₉PEO_1,2 + MeOH + Na]⁺ and doubly charged adducts [A₉PEO_>11 + 2 × Na]²⁺ were found.Molecular dynamics calculations showed that the A₉PEO_n molecule wraps itself around the complexing sodium ion in a way that negative electronic charges on oxygen have optimum electrostatic interaction with this ion. van der Waals interactions between alkyl chains are of less importance for the stability of these adducts. Both [2 × A₉PEO_2,5 + Na]⁺ dimer and [A₉PEO_2,5 + Na]⁺ monomer adducts turned out to be stable from an energetic point of view with adducts of A₉PEO₅ being more stable than adducts of A₉PEO₂. Only for the monomer adduct the latter is in accordance with experimental observations.Consequences of the formation of several adducts per A₉PEO_n oligomer for the quantitative analysis of environmental samples were evaluated. In clean samples, it was found that the presence of short-chain A₉PEO_1,2 can cause an overestimation of long-chain A₉PEO_>2. In real environmental extracts, other processes like matrix effects have a stronger influence on the quantitative result, and therefore no significant influence of adduct formation processes could be observed. However, inclusion of [A₉PEO_1,2 + MeOH + Na]⁺ adduct signals does improve the detection limits of the two short-chain oligomers.Correct quantitative results are obtained when A₉PEO₁ and A₉PEO₂ are quantified separately, and longer oligomers with a molar calibration followed by correction of the average molar weight of the A₉PEO_>2 in the sample.     

Conjugate addition of aromatic amines to ethenetricarboxylates

The conjugate addition of amines is considered to be a useful reaction in synthetic organic chemistry. The reaction of reactive electrophilic olefins, ethenetricarboxylates, and aromatic amines with and without catalytic Lewis acids such as ZnCl₂ and ZnBr₂ at room temperature gave amine adducts in high yields. The products were converted to α-amino acid, dl-aspartic acid derivatives. Using Lewis acids such as Sc(OTf)₃ and Zn(OTf)₂ at higher temperature (40-80 °C), the reaction of ethenetricarboxylates and N-methylaniline gave an aromatic substitution product. A catalytic enantioselective conjugate addition using a chiral Lewis acid was also investigated. For example, the reaction of 1,1-diethyl 2-tert-butyl ethenetricarboxylate with N-methylaniline in the presence of chiral bisoxazoline-Cu(II) complex in THF at −20 °C for 17 h gave an amine adduct in 91% yield and 78% ee. On the other hand, the reaction with aniline and primary aniline derivatives gave adducts with almost no ee%.     

Evaluation of polymer-supported vinyltin reagents in the Stille cross-coupling reaction

The synthesis of two new vinyltin reagents grafted on an insoluble macroporous polymer is reported. These reagents were used in the palladium-catalyzed Stille cross-coupling reaction with aryl halides. In all reactions, the conversion of the starting aryl halide is high and the amount of organotin by-product is particularly low (at the end of the catalytic run, the amount of Sn is up to 16 ppm in the crude reaction mixture removed of the insoluble polymer, and it is less than 1 ppm in the product purified by chromatography on silica gel).     

Site epimerization in ansa-zirconocene polymerization catalysts

Metallocene alkyl cations for polymerization of olefins possess two active sites involved in migratory insertion. Site epimerization, with an inversion at the metal atom, is considered to be one of the major causes for break-down of the alternating propagation model, resulting in stereoerrors whenever the two catalytic sites have substantially different enantioface selectivities. Density functional theory has been used to determine the intrinsic reaction coordinate that connects the optimized minima and transition states of inversion in the parent ansa-zirconocene [{H₂C(Cp)₂}Zr-Pr]⁺ (Pr = n-propyl). These calculations yield a three-step reaction path for site epimerization. Starting from the pyramidal β-agostic complex, an activated rotation around the Zr-Pr bond first produces an α-agostic conformation. Continued rotation leads to an equivalent second α-agostic intermediate and then finally to the inverted β-agostic complex. The second step is rate-determining and proceeds through a planar three-coordinate transition state. In the case of [{H₂C(Cp)₂}Zr-ⁱBu]⁺ (ⁱBu = iso-butyl), the situation is more complicated, because there are several interconvertible α-, β- and γ-agostic intermediates, but the rate-limiting step is again an inversion process connecting two different α-agostic conformers with the alkyl group on opposite enantiosides. For both ansa-zirconocene catalysts, the computed free-energy barriers for epimerization are around 11-12 kcal/mol and almost independent of temperature, while those for insertion increase with temperature due to the entropic cost of association. According to the computational results for the isolated catalysts, insertion remains favored over epimerization for the experimentally relevant temperature range in the n-propyl case, whereas both processes are competitive in the iso-butyl case. Inclusion of bulk solvent effects by a continuum solvation model does not affect the results much, while explicit consideration of a coordinating counterion causes larger changes. The present model calculations on the role of site epimerization should thus be most relevant for propene polymerization with non-coordinating counterions.     

Di(ethylene glycol) vinyl ether: a highly efficient deactivating reagent for olefin metathesis catalysts

A highly efficient method for deactivating commonly used olefin metathesis catalysts is described. Inexpensive and commercially available di(ethylene glycol) vinyl ether is found to quench both first- and second-generation Grubbs’ carbenes in less than 10 min at room temperature. The resulting ruthenium byproducts are readily removed by silica gel purification.     

A sol-gel immobilization of nano and micron size sorbents in poly(dimethylsiloxane) (PDMS) microchannels for microscale solid phase extraction (SPE)

Sorbent particles consisting of nano and micro silica, and micron size octadecylsilica (ODS) were immobilized using sol-gel chemistry onto poly(dimethylsiloxane) (PDMS) microfluidic channels to serve as μ-chip solid phase extraction (SPE) devices. Extraction, preconcentration and purification of biological and chemical analytes were carried out using these. Micro and nano scale silica-immobilized μ-SPE were used for the extraction/purification of DNA from recombinant Escherichia coli crude lysate. The average DNA recovery was 77 ± 9% (X ± R.S.D.) for the micron size silica particles and 70 ± 5% (X ± R.S.D.) for the nano silica particles. The extracted DNA could be amplified by polymerase chain reaction (PCR) whereas the DNA from the crude lysate solution could not be. This was a testimony to the purification capability of the μ-SPE device. ODS immobilized μ-SPE were used to study the extraction efficiency (EE) and enhancement factor (EF) for three groups of organic compounds, aromatics, phenols and carboxylic acids. They showed poor recovery and low enrichment because the analytes sorbed into the PDMS and were not quantitatively extracted.     

High-temperature synthesis of highly hydrothermal stable mesoporous silica and Fe-SiO2 using ionic liquid as a template

Mesoporous silicas and Fe-SiO₂ with worm-like structures have been synthesized using a room temperature ionic liquid, 1-hexadecane-3-methylimidazolium bromide, as a template at a high aging temperature (150-190 °C) with the assistance of NaF. The hydrothermal stability of mesoporous silica was effectively improved by increasing the aging temperature and adding NaF to the synthesis gel. High hydrothermally stable mesoporous silica was obtained after being aged at 190 °C in the presence of NaF, which endured the hydrothermal treatment in boiling water at least for 10 d or steam treatment at 600 °C for 6 h. The ultra hydrothermal stability could be attributed to its high degree of polymerization of silicate. Furthermore, highly hydrothermal stable mesoporous Fe-SiO₂ has been synthesized, which still remained its mesostructure after being hydrothermally treated at 100 °C for 12 d or steam-treated at 600 °C for 6 h.     

Determination of picomolar beryllium levels in seawater with inductively coupled plasma mass spectrometry following silica-gel preconcentration

A robust and rapid method for the determination of natural levels of beryllium (Be) in seawater was developed to facilitate mapping Be concentrations in the ocean. A solid-phase extraction method using a silica gel column was applied for preconcentration and purification of Be in seawater prior to determination of Be concentrations with inductively coupled plasma mass spectrometry (ICP-MS). Be was quantitatively adsorbed onto silica gel from solutions with pH values ranging from 6.3 to 9, including natural seawater. The chelating agent ethylenediamine tetraacetic acid was used to remove other ions in the seawater matrix (Na, Mg, and Ca) that interfere with the ICP-MS analysis. The reproducibility of the method was 3% based on triplicate analyses of natural seawater samples, and the detection limit was 0.4 pmol kg⁻¹ for 250 mL of seawater, which is sufficient for the analysis of seawater in the open ocean. The method was then used to determine the vertical profile of Be in the eastern North Pacific Ocean, which was found to be a recycled-type profile in which the Be concentration increased with depth from the surface (7.2 pmol kg⁻¹ at <200 m) to deep water (29.2 pmol kg⁻¹ from 3500 m to the bottom).     

Silica gel accelerated aza-Michael addition of amines to α,β-unsaturated amides

A novel method to synthesize β-amino amide has been developed via conjugated addition of amine to bulky α,β-unsaturated amides promoted by silica gel. The silica gel worked efficiently to accelerate the reaction and afforded the related adduct in good to excellent yield.     

Determination of aniline in silica gel sorbent by one-step in situ microwave-assisted desorption coupled to headspace solid-phase microextraction and GC-FID

Microwave-assisted desorption (MAD) coupled to in situ headspace solid-phase microextraction (HS-SPME) was first proposed as a possible alternative pretreatment of samples in absorbent collected from workplace monitoring. Aniline collected on silica gel was investigated. Under microwave irradiation, the aniline was desorbed from silica gel and directly absorbed onto the SPME fiber in the headspace. Having been sampled on the SPME fiber, and desorbed in the GC injection port, aniline was analyzed using a GC-FID system. Parameters that affect the proposed extraction efficiency, including the extraction media and its pH, the microwave irradiation power and the irradiation time as well as desorption parameters of the GC injector, were investigated. Experimental results revealed that the extraction of a 150-mg silica gel sample using a 0.8-ml aqueous solution (pH 12) and a PDMS/DVB fiber under medium-high-powered irradiation (345 W) for 3 min maximized the efficiency of extraction. Desorption of aniline from the SPME fiber was optimal at 230 °C held for 3 min. The detection limit was 0.09 ng. The proposed method provided a simple, fast, and organic solvent-free procedure to analyze aniline from a silica gel matrix.     

Convenient primary amidation of N-protected phenylglycine and dipeptides without racemization or epimerization

Primary amidation of N-protected phenylglycine and dipeptide proceeded easily to afford the corresponding amides in 57–95% yields with 99% ee and 81–99% de, respectively. The procedure is very easy to avoid racemization and epimerization of the products in the reactions by keeping exactly the reaction temperature at −15 °C when the activation of carboxylic acids, followed by the reaction of the mixed carbonic carboxylic anhydride with NH₄Cl.