Production Of Oxime Research Articles

A cleaner ammoximation of cyclohexanone over Ti-MWW in dimethyl carbonate

In this paper, dimethyl carbonate was selected as the solvent for the cyclohexanone ammoximation over Ti-MWW. Under the optimized reaction conditions, high conversion of cyclohexanone (99.8%) and high selectivity to oxime (99.6%) were achieved. The results of reuse of the catalyst showed that the Ti-MWW in this reaction system had better stability. Though the deactivation of the catalyst occurred after being used five times, the selectivity to cyclohexanone oxime was still kept above 99.9%, and calcining could easily recover catalytic activity. This work may provide a more environmentally benign solution for the industry production of cyclohexanone oxime.

Scandium(III) Triflate as a Lewis Acid Catalyst of Oxime Ligation

Imine-forming reactions are widely applicable in bioconjugation owing to their high chemoselectivity. The ligation of a ketone or aldehyde with an aminooxy functional group to form a physiologically stable oxime bond is often used to link complex and precious biomolecules. Although the reaction proceeds modestly in acidic solution, the abundance of protonated carbonyl species at pH 7 limits its utility in many biological applications. The use of nucleophilic aryl amines, such as aniline or a phenylenediamine, allows a high population of protonated Schiff base to undergo transimination to the oxime product. Although this method affords significant enhancements at low pH, reactions can still be sluggish at neutral pH, especially with ketones such as acetophenone that are commonly used in bioconjugation. Here, we employ scandium(iii) trifluromethanesulfonate (triflate) (Sc(OTf)3), a uniquely water-stable Lewis acid, as a co-catalyst with ortho-phenylenediamine in the oxime ligation to yield up to an order of magnitude rate enhancement over the catalysts when applied individually.

Formation and transformation of nitroso compounds of ketoxime isomers in ketone ammoximation catalyzed by hollow titanium silicalite

2-Nitrosopropane as the isomer of acetoxime was first found in ammoxidation of acetone with hydrogen peroxide catalyzed by hollow titanium silicalite (HTS). Experimental investigation indicates that the formation of 2-nitrosopropane was closely related to the pore size and surface acidity of HTS zeolite and significantly affected by reaction conditions, and further revealed that once formed, this isomer could be easily converted into main product acetoxime and also turned into by-product 2-nitropropane in the presence of excess hydrogen peroxide or O2. Based on the experimental results in combination with the analysis of reaction mechanism, it was suggested that the pathways of acetone ammoxidation catalyzed by HTS could involve both hydroxylamino intermediate and imino intermediate. The former was dominant in the production of acetone oxime, while the latter was mainly responsible for the formation of 2-nitropropane. In the latter case, an acetone first reacted with ammonia to form an imine and then interacted with an active center of Ti-OOH on catalyst to generate an unstable 2-nitrosopropane.

Improving the energy efficiency and production performance of the cyclohexanone ammoximation process via thermodynamics, kinetics, dynamics, and economic analyses

Abstract Cyclohexanone ammoximation is widely used as an efficient method to synthesize cyclohexanone oxime in industrial production. In this study, the cyclohexanone ammoximation production process was explored based on reaction kinetics in order to reduce its energy consumption and total annual cost. The effects of the reaction temperature, space time, and raw material ratios on the cyclohexanone oxime yield were analyzed. Under the optimized operating conditions, the maximum C6H11NO yield was 99.86%, and the minimum total annual cost was 5.988 × 107 $ per year. Dynamic control of the cyclohexanone ammoximation production process was further explored under the optimized conditions. The proposed control structure could achieve effective control and maintain the desired product yield when flow rate and composition disturbances were introduced. The energy and exergy analyses of the cyclohexanone ammoximation process show that its energy efficiency can be improved from a thermodynamic perspective. The combination of a steady state simulation and dynamic control, thermodynamic analysis, and economic performance evaluation provide insight into the improvement and operation of the cyclohexanone oxime production process.

Mesoporous silica gel as an effective and eco-friendly catalyst for highly selective preparation of cyclohexanone oxime by vapor phase oxidation of cyclohexylamine with air

A simple and environmentally benign approach to highly selective preparation of cyclohexanone oxime by vapor phase catalytic oxidation of cyclohexylamine with air over mesoporous silica gel under atmospheric pressure has been successfully developed in this work. The results demonstrate that the nonmetallic mesoporous silica gel is an effective and eco-friendly catalyst for the vapor phase selective oxidation of cyclohexylamine to cyclohexanone oxime and the surface silicon hydroxyl groups as active sites are responsible for the excellent catalytic performance of silica gel. The present silica gel catalyst has advantages of low cost, long-time stable reactivity, easy regeneration, and reusability. This method employing inexpensive mesoporous silica gel as catalyst and air as green terminal oxidant under facile conditions is a promising process and has the potential to enable sustainable production of cyclohexanone oxime from the selective oxidation of cyclohexylamine with air in industrial applications.

Oxime conjugation in protein chemistry: from carbonyl incorporation to nucleophilic catalysis.

Use of oxime forming reactions has become a widely applied strategy for peptide and protein bioconjugation. The efficiency of the reaction and robust stability of the oxime product has led to the development of a growing list of methods to introduce the required ketone or aldehyde functionality site specifically into proteins. Early methods focused on site-specific oxidation of an N-terminal serine or threonine and more recently transamination methods have been developed to convert a broader set of N-terminal amino acids into a ketone or aldehyde. More recently, site-specific modification of protein has been attained through engineering enzymes involved in posttranslational modifications in order to accommodate aldehyde-containing substrates. Similarly, a growing list of unnatural amino acids can be introduced through development of selective amino-acyl tRNA synthetase/tRNA pairs combined with codon reassignment. In the case of glycoproteins, glycans can be selectively modified chemically or enzymatically to introduce aldehyde functional groups. Finally, the total chemical synthesis of proteins complements these biological and chemoenzymatic approaches. Once introduced, the oxime ligation of these aldehyde and ketone groups can be catalyzed by aniline or a variety of aniline derivatives to tune the activity, pH preference, stability and solubility of the catalyst. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

DNA damage induced by carbon ions (C3+) beam accessed by independent component analysis of infrared spectra

Purpose: To understand the degradation processes and role of secondary species on deoxyribonucleic acid (DNA)-damaged fragments as a result of irradiation with energetic ions.Materials and methods: Damage caused to DNA thin films as a result of exposure to 4 keV carbon ions beam was accessed by analyzing the infrared spectra, obtained in situ for different irradiation times, with both bi-dimensional (2D) correlation spectroscopy and independent component analysis (ICA).Results: Results indicated that deoxyribose, phosphate and base groups of the DNA molecule were being damaged and new reaction products as oxime and furfural groups are being formed.Conclusions: Damage on DNA bases is consistent with the formation of oxime products which react with DNA deoxyribose products forming furfural groups and confirming that DNA damage is caused by direct and indirect processes.

Hydrazino-Pictet-Spengler Ligation as a Biocompatible Method for the Generation of Stable Protein Conjugates

Aldehyde- and ketone-functionalized biomolecules have found widespread use in biochemical and biotechnological fields. They are typically conjugated with hydrazide or aminooxy nucleophiles under acidic conditions to yield hydrazone or oxime products that are relatively stable, but susceptible to hydrolysis over time. We introduce a new reaction, the hydrazino-Pictet-Spengler (HIPS) ligation, which has two distinct advantages over hydrazone and oxime ligations. First, the HIPS ligation proceeds quickly near neutral pH, allowing for one-step labeling of aldehyde-functionalized proteins under mild conditions. Second, the HIPS ligation product is very stable (>5 days) in human plasma relative to an oxime-linked conjugate (∼1 day), as demonstrated by monitoring protein-fluorophore conjugates by ELISA. Thus, the HIPS ligation exhibits a combination of product stability and speed near neutral pH that is unparalleled by current carbonyl bioconjugation chemistries.

N–N Bond-Forming Cyclization for the One-Pot Synthesis of N-Aryl[3,4-d]pyrazolopyrimidines

An efficient one-pot synthesis of N-aryl[3,4-d]pyrazolopyrimidines in good yield and under mild reaction conditions is described. By exploiting electron-deficient hydroxylamines, the substituted oxime products were formed with very high E-diastereoselectivity. The key step utilizes a cyclization reaction upon an oxime derived from hydroxylamine-O-sulfonic acid to form the N–N bond of the product.

Oxime-based linker libraries as a general approach for the rapid generation and screening of multidentate inhibitors.

The described oxime-based library protocol provides detailed procedures for the linkage of aminooxy functionality with aldehyde building blocks that result in the generation of libraries of multidentate inhibitors. Synthesis of inhibitors for protein tyrosine phosphatases (PTPs) and antagonists directed against the human tumor susceptibility gene 101 (TSG101) are shown as examples. Three steps are involved: (i) the design and synthesis of aminooxy platforms; (ii) tethering with aldehydes to form oxime-based linkages with sufficient purity; and (iii) direct in vitro biological evaluation of oxime products without purification. Each coupling reaction is (i) performed in capped microtubes at room temperature (20-23 °C); (ii) diluted for inhibitory evaluation; and (iii) screened with targets in microplates to provide IC(50) or K(d) values. The synthesis of the aminooxy platforms takes 3-5 d; tethering with the aldehydes takes 24 h; and inhibition assay of enzymes and protein-protein interactions takes 30 min and 2 h, respectively.

Temperature-Dependent Solid-State Electron Transport through Bacteriorhodopsin: Experimental Evidence for Multiple Transport Paths through Proteins

Electron transport (ETp) across bacteriorhodopsin (bR), a natural proton pump protein, in the solid state (dry) monolayer configuration, was studied as a function of temperature. Transport changes from thermally activated at T > 200 K to temperature independent at <130 K, similar to what we have observed earlier for BSA and apo-azurin. The relatively large activation energy and high temperature stability leads to conditions where bR transports remarkably high current densities above room temperature. Severing the chemical bond between the protein and the retinal polyene only slightly affected the main electron transport via bR. Another thermally activated transport path opens upon retinal oxime production, instead of or in addition to the natural retinal. Transport through either or both of these paths occurs on a background of a general temperature-independent transport. These results lead us to propose a generalized mechanism for ETp across proteins, in which tunneling and hopping coexist and dominate in different temperature regimes.

Determination of sphingosine-1-phosphate lyase activity by gas chromatography coupled to electron impact mass spectrometry

Sphingosine-1-phosphate lyase (SGPL1) is the last enzyme in the catabolism of sphingolipids. It catalyzes the retroaldolic cleavage of long chain base phosphates into phosphoethanolamine and a fatty aldehyde. In this article we report on an easy and sensitive procedure to determine SPL activity. The assays uses C17-sphinganine-1-phosphate as substrate and the aldehyde product, pentadecanal, is quantified as its pentafluorobenzyloxime derivative by GC/MS. Derivatization of pentadecanal is performed as a one-step reaction, and the oxime product is directly injected for GC/MS analysis without any further purification. Acquisition in selected ion monitoring mode allows very high sensitivity, with a limit of detection of 281fmol. The assay is linear with both protein concentration and incubation time up to 20μg and 40min, respectively. The Km value obtained (6μM) is similar to that for the natural substrate sphingosine-1-phosphate. Using this method, FTY720 and deoxypyridoxine phosphate inhibited SPL with similar potencies to those reported.

ChemInform Abstract: Synthesis, Biological Activity and Metabolism of N-Hydroxytryptophan.

Abstract N -Hydroxytryptophan (α-hydroxyamino-β-indolyl-3-propionic acid) was chemically synthesized. On a mole basis, its relative biological activity in comparison with indole-3-acetic acid at sub-optimal concentrations is: oat coleoptile curvature test=0.129; oat first internode test=0.089 and linseed root growth inhibition test=0.022. Infiltration of N -hydroxytryptophan into oat coleoptile sections leads to the production of indoleacetaldehyde oxime, indoleacetaldehyde and indoleacetic acid. It is suggested that tryptophan could be metabolized in oat coleoptiles to indole-3-acetic acid via N -hydroxytryptophan, indoleacetaldehyde oxime and indoleacetaldehyde.

Continuous Acetone Ammoximation over TS-1 in a Tubular Membrane Reactor

A new tubular membrane reactor based on tubular metallic membrane is developed, which can solve the problem concerning in situ separation of catalyst from the reaction mixture and make the production process continuous. In this article, the feasibility of continuous ammoximation of acetone to acetone oxime over titanium silicalites-1 (TS-1) in the tubular membrane reactor was investigated. It has demonstrated that the tubular membrane reactor system can maintain a more long-term steady production of acetone oxime than that of a side-stream ceramic membrane reactor and has a higher productivity than the batch reactor. The effects of operation conditions (stirring rate, residence time, temperature, catalyst concentration, molar ratio of NH3/acetone, H2O2/acetone, and t-butanol/acetone) on the performances of the reaction system were examined via single factor experiments. Results show that the operation conditions greatly affect the conversion, selectivity of acetone ammoximation, and the filtration resista...

Selective Tethering of Ligands and Proteins to a Microfluidically Patterned Electroactive Fluid Lipid Bilayer Array

We report a new, quantitative methodology to pattern and present ligands from planar, supported, fluid lipid bilayers. By combining microfluidic lithography (microFL) with an electroactive, chemoselective interfacial reaction strategy, a number of ligands as well as protein concanavalin A were immobilized in lipid microarrays. Electroactive vesicles were generated after the spontaneous insertion of hydroquinone-tethered alkane (H(2)Q) into egg palmitoyl-oleoyl phosphatidylcholine (egg-POPC), followed by subsequent fusion to a siloxane-terminated self-assembled monolayer (SAM) on gold. An advantage of the H(2)Q system is that it can be electrochemically oxidized to the corresponding quinone (Q), followed by rapid chemoselective conjugation with oxyamine-functionalized (RONH(2)) ligands. The oxime product is also electroactive, and the reaction can be monitored and the amount of ligand bound can be quantified by electrochemistry. The bilayers were characterized by electrochemistry, fluorescence microscopy, and ellipsometry and were determined to be fluid by fluorescence recovery after photobleaching (FRAP). This strategy provides a synergistic method to pattern and present a number of ligands or biomolecules from the bilayer surface for the evaluation of enzyme or protein binding to biomembranes.

Single-site catalysts and cleaner production processes, the case of TS-1

The synthesis of Titanium Silicalite-1 (TS-1) made possible the development of new oxidation processes, environmentally clean and economically convenient. First industrial application, in 1986, was the hydroxylation of phenol to hydroquinone and catechol (10,000 t/a). In 2003, the production of cyclohexanone oxime became operative within an integrated process for the manufacture of ∈-caprolactam by an entirely new technology (60,000 t/a). The overall process is salt-free and with minimal gaseous emissions. In 2006, the construction of a 300,000 t/a plant for propylene oxide started in Belgium and others have been planned in the world. All three processes utilize hydrogen peroxide produced by the conventional anthraquinone process. Parallel to this, however, an intense research is in progress on the direct synthesis of the oxidant from the elements, to simplify the process and reduce the H2O2 production costs. Other means to achieve the same objectives are process integration, in the short term, andin situ generation, in the longer one. TS-1, on the other hand, will likely remain unrivalled catalyst for many years to come. The metal substituted zeolites, that in last two decades have been prepared in a large number, are catalytically inferior and inadequate to possible industrial applications.

Development and Industrialization of the Vapor-Phase Beckmann Rearrangement Process

Abstract The development of a new catalyst effective for the vapor-phase Beckmann rearrangement of cyclohexanone oxime has made it possible to establish a commercial process for the production of ε-caprolactam without producing any ammonium sulfate. Through fundamental studies of the catalyst, it was discovered that an MFI-type zeolite composed exclusively of silica had a high selectivity and activity for the vapor-phase Beckmann rearrangement. Based on acidity measurements and on the reactivity of oximes with different sizes as well as the calculation results of the deprotonation energies of some silanols, we have suggested that the active sites are nest silanols located close to their mouth of the micro pores. By addition of methanol into the reaction system, the selectivity for ε-caprolactam was markedly improved to the levels required for industrialization. A fluidized bed reactor was used for the reaction system in order to maintain a continuous production. By combining the ammoximation process for production of cyclohexanone oxime using the TS-1 catalyst and the vapor-phase Beckmann rearrangement, a commercial plant has been operating on a 60000 tons per year scale since April 2003, without any troubles.

GC‐MS analysis of multiply derivatized opioids in urine

Opiates such as hydrocodone, hydromorphone, oxycodone, noroxycodone, and oxymorphone reportedly may interfere with the analysis of morphine and codeine. The analysis of these compounds themselves also is an important issue. Thus, double derivatization approaches utilizing methoxyamine and hydroxylamine to first form oxime products with keto-opiates, followed by the derivatization with trimethylsilyl (TMS) or propionyl groups, have been developed for the simultaneous analysis of these compounds. However, these studies have not included all compounds of interest and resulted in inadequate chromatographic resolution or significant intensity cross-contribution between the ions designating the analyte and its deuterated internal standard for certain compounds. By exploring three-step derivatization approaches with the combination of various derivatization groups and orders, this study concluded that application of methoxyimino/propionyl/TMS groups, in the order listed, facilitated the simultaneous analysis of eight opiates (morphine, 6-acetylmorphine, hydromorphone, oxymorphone, codeine, hydrocodone, oxycodone and noroxycodone) in urine samples, achieving satisfactory limits of quantitation and detection. In addition, the adapted approach resulted in two usable products for morphine and codeine providing alternatives, should interferences render any of these products non-usable.

6-Oxo-Morphinane Oximes: Pharmacology, Chemistry and Analytical Application

The permanent therapeutic importance of morphine derivatives in pain treatment has inspired continual synthetic efforts to modify the rigid pentacyclic systems in search for new selective analgesic agents. As a result, several morphinane oximes have been synthesized recently, which have the additional advantage of possessing an oxime group that can provide a method for selective determination of opiate alkaloids in biological matrices. The oximes of hydrocodone and oxycodone have stronger analgesic effect than the parent ketones and they also proved to be effective in preventing the respiratory depressant and hypotensive actions of fentanyl. In this work a review is given on the present status of oxime pharmacology, chemistry and analysis and also the oxime and O-methyl oxime formation of 6-oxo-morphinanes with therapeutic interest (codeinone, oxycodone, hydrocodone and 14-OH-codeinone). The oxime formation was monitored by reversed-phase HPLC and the chromatographic properties of oxime isomers have been characterized. The assignation of the individual isomers isolated by preparative HPLC was performed by (1)H NMR spectroscopy based on the chemical shift differences of the 5-H signals. In this way the isomeric ratio in the oxime products could also be determined. It was found that in the case of Delta(7)-6-oxo-morphinanes, depending on the substituents, the formation of the Z-isomer highly dominates (73-96%) over that of the E-isomer. However, for the saturated 7,8-(dihydro) derivatives the E-isomer is definitely preferred (>98%). In conclusion of a survey on the theoretical background of oxime isomerism, the conformational differences between the saturated and unsaturated morphinane systems were found responsible for the different E/Z ratios. On the basis of the isomeric ratio and the on-line CD and UV spectra of the pure isomers, the molar ellipticities and absorbancies of the isomers were calculated by a parameter estimation method.

Integrated Process of H2O2 Generation through Anthraquinone Hydrogenation−Oxidation Cycles and the Ammoximation of Cyclohexanone

The liquid−liquid-phase equilibrium of a five-component system of methanol−water−H2O2−trimethylbenzene−trioctyl phosphate was studied, and the data were correlated with UNIQUAC and NRTL models, respectively, and used for the simulation of the extraction of H2O2 with an aqueous methanol solution in the H2O2 production process based on anthraquinone hydrogenation−oxidation cycles. The results showed that, with an aqueous methanol solution for the extraction of H2O2, after a few cycles the concentration of methanol in an anthraquinone working solution becomes constant and would not influence the H2O2 production process. All of the impurities in the H2O2 solution obtained with an aqueous methanol solution as the extractant from the H2O2 generation process as well as the stabilizers and corrosion inhibitors that should be added in the H2O2 solution did not appreciably affect the direct ammoximation of cyclohexanone with NH3 and H2O2 catalyzed by TS-1. The results indicated that the processes of cyclohexanone oxime production through the direct ammoximation of cyclohexanone and H2O2 generation through the anthraquinone hydrogenation−oxidation cycles could be integrated.