Isomeric Products Research Articles

Intensification of an Irreversible Process Using Reactive Distillation – Simulation Studies

Abstract: In this study, a steady state simulation of the process for the production of xylene isomers by reactive distillation was performed using Aspen Plus software. The simulations were aimed studying the parameters like number of stages in the different sections of the RD column, reflux ratio, and the boil-up ratio, which maximize the conversion of Toluene and improves the selectivity and yield of the p- Xylene. Keywords: Reactive Distillation, Process Intensification, Toluene Methylation, Aspen Plus, Simulation Studies,

Ion mobility spectrometry-tandem mass spectrometry strategies for the on-line monitoring of a continuous microflow reaction

Continuous flow chemistry is an efficient, sustainable and green approach for chemical synthesis that surpasses some of the limitations of the traditional batch chemistry. Along with the multiple advantages of a flow reactor, it could be directly connected to the analytical techniques for on-line monitoring of a chemical reaction and ensure the quality by design. Here, we aim to use ion mobility, mass and tandem mass spectrometry (IMS-MS and MS/MS) for the on-line analysis of a pharmaceutically relevant chemical reaction. We carried out a model hetero-Diels Alder reaction in a microflow reactor directly connected to the IMS-MS and MS/MS using either electrospray or atmospheric pressure photo ionization methods. We were able to monitor the reaction mechanism of the Diels Alder reaction and structurally characterize the reaction product and synthesis side-products. The chosen approach enabled identification of two isomers of the main reaction product. A new strategy to annotate the ion mobility spectrum in the absence of standard molecules was introduced and tested for its validity. This was achieved by determining the survival yield of each isomer upon ion mobility separation and density functional theory calculations. This approach was verified by comparing the theoretically driven collision cross section values to the experimental data. In this paper, we demonstrated the potential of combined IMS-MS and MS/MS on-line analysis platform to investigate, monitor and characterize structural isomers in the millisecond time scale.

Stereoconvergent and -divergent Synthesis of Tetrasubstituted Alkenes by Nickel-Catalyzed Cross-Couplings.

We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling.

Dearomatization of 2,3-Disubstituted Indoles via 1,8-Addition of Propargylic (Aza)-para-Quinone Methides.

Dearomatization of indole is a useful strategy to access indolimines: a motif widely exists in biologically active molecules and natural products. Herein, an efficient method for the dearomatization of 2,3-disubstituted indoles to generate diverse indolimines with tetrasubstituted allenes is described. This work accomplishes dearomatization of 2,3-disubstituted indoles through 1,8-addition of (aza)-para-quinone methides, which are generated in situ from propargylic alcohols. A series of synthetically useful indolimines containing quaternary carbon centers and tetrasubstituted allenes can be accessed in good yields (up to 99%). Additionally, the separability of product isomers, diversified product transformations, and easy scale-up of the reaction demonstrate the potential application of this method.

Bio-refinery of plant drinks press cake permeate using ultrafiltration and lactobacillus fermentation into antimicrobials and its effect on the growth of wheatgrass in vivo

For sustainable plant drinks production, the biorefinery concept of obtained press cakes (PC) using ultrasonication, mechanical separation, and ultra-filtration was designed in Fraunhofer UMSICHT (Germany). In this study obtained permeates, as wastes after ultrafiltration of PC (soyabeans, almonds, coconut, oats, and rice) were analyzed and their bio-stimulatory effect on the growth of wheatgrass in vivo was investigated. Permeates with higher soluble protein content (soy, almonds, and coconut) resulted in a significant increase in germination parameters (germination percentage (GP), length of stem and root as well as biomass of stem and root increased on averge by 8.3%, 15.8%, 9.2%, 2.22 times and 1.8 times, respectively) compared to the control treatment. Additionally, the fermentation using antimicrobial lactic acid bacteria (LAB) strains (Lactobacillus brevis LUHS173, Pediococcus acidilactici LUHS236 and Lactobacillus farraginis LUHS206) was applied for bio-treatment of permeates. The efficiency of fermentation process was evaluated on the changes of pH, TTA, LAB growth kinetics and lactic acid and its isomers production. Furthermore, the antifungal activity of selected fermented products against fungi (Fusarium graminearum F, F. graminearum, and F. culmorum) was determined. It was found that the highest antifungal activity (18.0 mm and 16.5 mm, respectively) was obtained by 48 h fermentation of permeates from grain press cake (oats and rice), containing the most reducing saccharides, and they significantly improved the germination of contaminated grains. Innovations in the sustainable production of plant-origin drinks enable to implementation of new, environmentally friendly technologies in food sector.

Microreaction and membrane technologies for continuous single-enantiomer production: A review

ABSTRACT Microreaction and membrane technologies offer optimal conditions for controlling enantiomer synthesis and purification processes in continuous production, with numerous advantages over batch manufacturing. One of the many forces driving the development of such technologies for the production of single optical isomers is the need for enantiomerically pure pharmaceutical drugs because enantiomers may display opposite therapeutic effects or different treatment efficacies and side effects. Yet, despite advances in asymmetric synthesis and separation techniques, preparing enantiomerically pure compounds remains a challenging task. Here, we review the progress in microfluidics and membrane chiral separation over the last two decades. In addition to describing and critically assessing the state of the art in both disciplines, we provide an overview of their beneficial properties and characteristics for developing technologies toward producing enantiomerically pure compounds. Concomitantly, we evaluate efforts to integrate synthesis and membrane separation into a microfluidic platform and pinpoint the limiting factors that must be overcome before these platforms can be fully deployed in the industry.

Carbocation Footprinting of Soluble and Transmembrane Proteins

Here, we introduce carbocations (R3C+) as laser-initiated footprinting reagents for proteins. We screened seven candidates and selected trifluomethoxy benzyl bromide (TFBB) as an effective precursor for the electrophilic trifluomethoxy benzyl carbocation (TFB+) under laser (248 nm) irradiation on the fast photochemical oxidation of proteins (FPOP) platform. Initial results demonstrate that this electrophilic cation reagent affords residue coverage of nucleophilic amino acids including H, W, M, and S. Further, the addition of TFB+ increases the hydrophobicity of the peptides so that separation of isomeric peptide products by reversed-phase LC is improved, suggesting opportunities for subresidue footprinting. Comparison of apo- and holo-myoglobin footprints shows that the TFB+ footprinting is sensitive to protein conformational change and solvent accessibility. Interestingly, because the TFB+ is amphiphilic, the reagent can potentially footprint membrane proteins as demonstrated for vitamin K epoxide reductase (VKOR) stabilized in a micelle. Not only does footprinting of the extra-membrane domain occur, but also some footprinting of the hydrophobic transmembrane domain is achieved owing to the interaction of TFB+ with the micelle. Carbocation precursors are stable and amenable for tailoring their properties and those of the incipient carbocation, enabling targeting their soluble or membrane-associated or embedded regions and distinguishing between the extra- and trans-membrane domains of membrane proteins.

Comprehensive LC-HRMS metabolomics analyses for the estimation of environmental inputs of altrenogest in pig breeding

Altrenogest (ALT), a synthetic progestogen, is used in pig farming for estrus synchronization in gilts. Residues of ALT and its metabolites may reach the aquatic environment via the spread of liquid manure and may present a risk for fish and other higher aquatic organisms due to its endocrine disrupting potential. A pilot study was conducted in which spot urine samples from ALT-treated and non-medicated gilts were collected. We applied LC-HRMS analysis to perform targeted analysis of ALT and known metabolites as well as non-targeted metabolomics analyses to find previously unknown metabolites. The targeted investigation showed that glucuronide conjugates of ALT and its photo-isomerization product are main urinary metabolites of ALT in gilts. Furthermore, an unknown isomerization product of ALT was observed at trace level, whereas ALT and ALT sulfate were not found. The chemometric analysis of non-targeted data revealed a clear difference between ALT-treated gilts and control animals. Furthermore, a hydroxylated ALT glucuronide was identified as highly significant in the ALT-treated group. Additional biomarker annotation and pathway mapping revealed changes in the metabolism of ALT-treated animals which can be explained by ALT's hormonal action. This study illustrates the exceptional potential of LC-HRMS and metabolomics for the detection of potentially new environmental contaminants with high biological activity. Further advantages of the method described are the sampling during routine breeding conditions, a relatively small number of animals required and no particular stress for the animals.

A heavy-ion production channel of 149Tb via 63Cu bombardment of 89Y

The radionuclide 149Tb (t1/2 = 4.1 h) is a potential theranostic isotope which can simultaneously be used for targeted-alpha-particle therapy and positron-emission tomography. Feasibility experiments were performed to test a near-symmetric heavy-ion reaction of 63Cu bombardment on monoisotopic 89Y. The indirect reaction was studied to avoid isomer production. Offline gamma spectroscopy was used to quantify thick-target physical yields and experimental results show modest agreement to the fusion-evaporation code PACE4. A near-symmetric fission yield was also observed.

Update of the Planktonic Diatom Genus Pseudo-nitzschia in Aotearoa New Zealand Coastal Waters: Genetic Diversity and Toxin Production.

Domoic acid (DA) is produced by almost half of the species belonging to the diatom genus Pseudo-nitzschia and causes amnesic shellfish poisoning (ASP). It is, therefore, important to investigate the diversity and toxin production of Pseudo-nitzschia species for ASP risk assessments. Between 2018 and 2020, seawater samples were collected from various sites around Aotearoa New Zealand, and 130 clonal isolates of Pseudo-nitzschia were established. Molecular phylogenetic analysis of partial large subunit ribosomal DNA and/or internal transcribed spacer regions revealed that the isolates were divided into 14 species (Pseudo-nitzschia americana, Pseudo-nitzschia arenysensis, Pseudo-nitzschia australis, Pseudo-nitzschia calliantha, Pseudo-nitzschia cuspidata, Pseudo-nitzschia delicatissima, Pseudo-nitzschia fraudulenta, Pseudo-nitzschia galaxiae, Pseudo-nitzschia hasleana, Pseudo-nitzschia multiseries, Pseudo-nitzschia multistriata, Pseudo-nitzschia plurisecta, Pseudo-nitzschia pungens, and Pseudo-nitzschia cf. subpacifica). The P. delicatissima and P. hasleana strains were further divided into two clades/subclades (I and II). Liquid chromatography-tandem mass spectrometry was used to assess the production of DA and DA isomers by 73 representative strains. The analyses revealed that two (P. australis and P. multiseries) of the 14 species produced DA as a primary analogue, along with several DA isomers. This study is the first geographical distribution record of P. arenysensis, P. cuspidata, P. galaxiae, and P. hasleana in New Zealand coastal waters.

Helical Bisphosphinites in Asymmetric Tsuji‐Trost Allylation: a Remarkable P:Pd Ratio Effect

AbstractThis article discloses a study on a chiral bis‐phosphorylated‐helical ligand in the palladium‐catalyzed Tsuji‐Trost allylation. The use of 2,15‐bisphosphinite‐[6]‐helicenes revealed a remarkable ligand effect, in which the (R) and (S) isomeric products can be selectively formed as a direct function of the amount of ligand introduced. Investigation of the organometallic species involved through 31P NMR spectroscopic analysis of a model complex and X‐Ray diffraction analysis together with DFT calculations shed light on this phenomenon.

Synthesis of Palladium and Copper Nanoparticles Supported on TiO2 for Oxidation Solvent-Free Aerobic Oxidation of Benzyl Alcohol

The use of metal oxides as supports for palladium and copper (Pd–Cu) nanoalloys constitutes a new horizon for improving new active catalysts in very important reactions. From the literatures, Pd-based bimetallic nanostructures have great properties and active catalytic performance. In this work, nanostructures of titanium dioxide (TiO2) were used as supports for Pd–Cu nanoparticles catalysts. Palladium and copper were deposited on these supports using the sol-immobilisation method. The composite nanoalloys were characterized using transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). The catalyst was evaluated for the oxidation of benzyl alcohol. The effect of the Cu–Pd ratio using sol-immobilization methods supported on TiO2 was investigated. The results show that monometallic Cu/TiO2 was observed to have a low activity. However, as soon as the catalyst contained any palladium, the activity increased with a significant increase in the selectivity towards isomerization products. The influence of support and temperature were investigated. Furthermore, the catalyst reusability was also tested for oxidation of benzyl alcohol reactions, by repeatedly performing the same reaction using the recovered catalyst. The Pd–Cu/TiO2 catalyst displayed better reusability even after several reactions

Enhancing the Catalytic Properties of Mordenites via an Alkali-Acid Treatment and by Loading Nickel-Cerium during o-Ethyltoluene Isomerization.

The catalytic performance of the selective isomerization of o-ethyltoluene (O-ET) is crucial to increasing the m-ethyltoluene (M-ET) and p-ethyltoluene (P-ET) yields. During the isomerization of O-ET, traditional (commercial) mordenites (HM) are generally limited by a high reaction temperature (235 °C), as well as a low yield of the isomerization product (49.0%). In this study, micro-mesoporous mordenites were obtained by treating commercial mordenites with NaOH, NaOH–HNO3, and NaOH–mixed acid (HNO3–oxalic). Thereafter, their structure, porosity, and acidity were investigated via X-ray diffraction, transmission electron microscopy, inductively coupled plasma, N2 sorption, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy of pyridine, temperature-programmed desorption of ammonia, and nuclear magnetic resonance. Among the various treated samples, the accessibility of the acidic sites and the B/L value of the alkali–mixed HNO3–oxalic one were enhanced, achieving the highest yield (53.6%) and lowest reaction temperature (165 °C), thus significantly reducing the energy consumption of the reaction process. Furthermore, Ni and Ce were successfully loaded via the incipient wetness impregnation of the micro-mesoporous mordenite to significantly prolong the catalytic life. This study affords a new strategy for obtaining high M-ET and P-ET yields from the isomerization of O-ET in mixed C9 aromatics on an industrial scale.

Isomerization of a cis-(2-Borylalkenyl)Gold Complex via a Retro-1,2-Metalate Shift: Cleavage of a C-C/C-Si Bond trans to a C-Au Bond.

This manuscript describes the first example of an alkyne insertion to the Au-B bond of a di(o-tolyl)borylgold complex to afford a cis-2-borylalkenylgold complex, and its isomerization to result in interchanging substituents on the alkenyl carbon atom and the boron atom. The former reaction is the first example of an alkyne insertion to a Au-B bond. In the latter reaction, the regiochemistry of the isomerized alkenylgold products varied depending on the substituents. DFT calculations revealed the formation of gold alkynylborates as a common intermediate via a "retro-1,2-metalate shift", which can be considered as an anti-β-carbon/silicon elimination, and identified a subsequent 1,2-metalate shift as the regiochemistry-determining step. Relative energies of the transition states to each isomer and natural-bond-orbital (NBO) analyses were used to clearly rationalize the regiochemistry of the products.

Isomerization of a cis‐(2‐Borylalkenyl)Gold Complex via a Retro‐1,2‐Metalate Shift: Cleavage of a C−C/C−Si Bond trans to a C−Au Bond

AbstractThis manuscript describes the first example of an alkyne insertion to the Au−B bond of a di(o‐tolyl)borylgold complex to afford a cis‐2‐borylalkenylgold complex, and its isomerization to result in interchanging substituents on the alkenyl carbon atom and the boron atom. The former reaction is the first example of an alkyne insertion to a Au−B bond. In the latter reaction, the regiochemistry of the isomerized alkenylgold products varied depending on the substituents. DFT calculations revealed the formation of gold alkynylborates as a common intermediate via a “retro‐1,2‐metalate shift”, which can be considered as an anti‐β‐carbon/silicon elimination, and identified a subsequent 1,2‐metalate shift as the regiochemistry‐determining step. Relative energies of the transition states to each isomer and natural‐bond‐orbital (NBO) analyses were used to clearly rationalize the regiochemistry of the products.

Data-science driven autonomous process optimization

Autonomous process optimization involves the human intervention-free exploration of a range process parameters to improve responses such as product yield and selectivity. Utilizing off-the-shelf components, we develop a closed-loop system for carrying out parallel autonomous process optimization experiments in batch. Upon implementation of our system in the optimization of a stereoselective Suzuki-Miyaura coupling, we find that the definition of a set of meaningful, broad, and unbiased process parameters is the most critical aspect of successful optimization. Importantly, we discern that phosphine ligand, a categorical parameter, is vital to determination of the reaction outcome. To date, categorical parameter selection has relied on chemical intuition, potentially introducing bias into the experimental design. In seeking a systematic method for selecting a diverse set of phosphine ligands, we develop a strategy that leverages computed molecular feature clustering. The resulting optimization uncovers conditions to selectively access the desired product isomer in high yield.

Isomerization and hydroformylation of butenes under the catalysis of Rh-BIPHEPHOS

The isomerization and hydroformylation of butene under the catalysis of Rh-BIPHEPHOS were investigated by varying the butene feed and reaction temperature. The results indicate that in the presence of syngas, with 1-butene as feed, more isomerization product (i.e. 2-butene) is detected in comparison with the hydroformylation products, whereas with 2-butene as the feed, the hydroformylation is superior to isomerization. Due to the equilibrium limit between 1-butene and 2-butene, the increase of temperature shows a great positive effect on the isomerization reaction. Furthermore, under the catalysis of Rh-BIPHEPHOS, more n-pentanal is always formed than i-pentanal, as the larger bite angle of BIPHEPHOS restricts the intermediate rearrangement in the formation of i-pentanal.

Structural Diversity in the Reactions of Dimetallic Alkyl Titanium Oxides with Isonitriles and Nitriles

A detailed study of the reaction of the dinuclear [{Ti(η5-C5Me5)R2}2(μ-O)] (R = Me 1, CH2Ph 2) compounds with a series of organic isonitriles (R′NC, R′ = tBu, iPr, CH2SiMe3, Xyl) (Xyl = 2,6-Me2C6H3) and nitriles (R′CN, R′ = tBu, iPr, SiMe3) has been carried out. Single-crystal X-ray structural studies revealed a variety of reactivity and structural moieties. Theoretical calculations (density functional theory, DFT) were used to understand the mechanism of some uncommon reactions observed experimentally. Reactions of 1 and 2 with isocyanides tBuNC, iPrNC, and Me3SiCH2NC led to the formation of dimetallic η2-iminoacyl species [{Ti(η5-C5Me5)(R′NCR)R}2(μ-O)] (R = Me, R′ = tBu 3, iPr 4, CH2SiMe3 5; R = CH2Ph, R′ = CH2SiMe3 6). Complex 4 underwent net rearrangements at room temperature to give the imido-vinylamido derivative [Ti2(η5-C5Me5)2(μ-O)(μ-NiPr) {N(iPr)CMe═CMe2}Me] (7), whereas the reaction of complex 2 with XylNC rendered the N─C bond cleavage product [{Ti(η5-C5Me5)(CH═CHPh)}(μ-O)(μ-κ2-N,C─N(MeC6H3)CH2){Ti(η5-C5Me5)}] (8). The reactions of 1 with nitriles tBuCN and iPrCN gave the ketimido products [{Ti(η5-C5Me5)Me(CN(Me)R′)}2(μ-O)] (R′ = tBu 9, iPr 10), whereas the analogous processes with 2 gave the alkenyl-imido complexes [{Ti(η5-C5Me5)(CH2Ph)2}(μ-O){Ti(η5-C5Me5)(═NC(R′)═C(H)Ph)(NCR′)}] (R′ = tBu 11, iPr 12) with the concomitant coordination of a nitrile molecule. Complex 1 reacts with Me3SiCN to afford the nitrile–isonitrile isomerization product [{Ti(η5-C5Me5)Me2}(μ-O){Ti(η5-C5Me5)(κ2-C,N-Me2CNSiMe3)(CNSiMe3)] (13).

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Efficient HPLC Separation on a Core-C30 Column with MS2 Characterization of Isomers, Derivatives and Unusual Carotenoids from Tomato Products.

An efficient and rapid liquid chromatographic method was developed for the separation of carotenoids and their geometrical isomers in tomato products using a core C30 column of 2.6μm particles with gradient elution of tert-butyl-methyl-ether in 2% water in methanol. Excellent separation of the major carotenoids such as lycopene, β-carotene and lutein as well as their geometrical isomers and oxygen-containing derivatives with resolution factors ranging between 0.78 and 4.0 and selectivity of 1.01-1.63 was achieved. Validation of the developed method met the acceptance criteria concerning linearity, recovery, precision and limit of detection and quantification. Calibrations were linear with correlation coefficient (R2) values between 0.9966 and 0.9999. The limit of detection and quantification values were found to be 0.008 and 0.017 and 0.029 and 0.056μg/mL, respectively. Recovery of 94.3-99.9%, intraday precision of 1.81-4.45% and interday precision of 3.13-6.86% were obtained. The hyphenation of liquid chromatography with diode-array and mass spectrometry was helpful in the identification of the separated carotenoids particularly the unusual di-hydroxy cyclolycopene adduct and di-methoxy lycopene determined for the first time in tomato products. Commercially available kinds of tomato juice and ketchup were evaluated based on their carotenoid content.