Crude Reaction Mixture Research Articles

Size Selectivity in the Hydroxylation of Esters of Unsaturated Fatty Acids

AbstractThe one‐pot two‐steps hydroxylation of fatty acid esters with H2O2 and acetic acid catalyzed by acidic ion exchange resins is reinvestigated aiming to shed light on the relationship between the structure of different substrates and the efficiency of different resins in promoting the hydrolysis of the intermediate epoxides to the corresponding diols. 1H‐NMR analysis of crude reaction mixtures highlight a correlation between the drying process of the resins, their cross‐linking degree, and their effectiveness in promoting such a hydrolysis. Employing dry Dowex 50WX2 as a catalyst, a close relationship is found between the steric hindrance of the substrates and the recovered diol/epoxide ratio, with less hindered substrates preferentially leading to the formation of high diol/epoxide ratios. Accordingly, this procedure is successfully applied to the valorization of the methyl ester of a waste cooking oil. Conversions and selectivity kinetics increase significantly when the amount of the catalyst is increased leading to successfully apply this one‐pot two‐steps hydroxylation reaction to esters of unsaturated fatty acids sterically bulkier than methyl oleate. Spectroscopic and morphological characterization of Dowex 50WX2 shows that the drying process and the interaction with the reagents affect the morphology of the catalyst and promotes the hydrolysis of the intermediate epoxides.Practical applications: Hydroxylated fatty acids are valuable intermediates in the synthesis of a variety of useful biochemicals, including mono‐ and di‐carboxylic acids, biolubricants, and cosmetics. Their work describes the successful application to a variety of esters of unsaturated fatty acids and to the methyl esters of a vegetable oil and a waste cooking oil, of a straightforward hydroxylation procedure, catalysed by commercially available acidic ion exchange resins and occurring under mild and easy to set‐up conditions. The evidence reported on the different catalytic activities and on the structural characterization of the as‐received and dried acidic ion exchange resins are of practical importance in their employment as acidic catalysts.

One-Pot Glycosylation Strategy Assisted by Ion Mobility-Mass Spectrometry Analysis toward the Synthesis of N-Linked Oligosaccharides.

N-Glycans are major constituents of several cellular glycoproteins. One-pot strategies for the synthesis of N-glycans are crucial for the rapid generation of pure samples to determine their biological functions. Herein, we describe a double one-pot strategy for the synthesis of N-glycans assisted by an IM-MS analysis approach for rapid screening of optimized glycosylation reaction conditions. This research includes triflate-mediated direct β-mannosylation and tandem glycosylation in a one-pot strategy for the synthesis of the challenging N-linked trisaccharide core β-5. Furthermore, a one-pot sequential glycosylation of the N-linked trisaccharide core 7 furnishes diverse high-mannose type N-glycans with excellent stereo- and regioselectivities. In particular, ion mobility-mass spectrometry-based quantitative analysis is applied to identify the stereo- and regioselective outcomes of the crude reaction mixtures to develop a highly efficient one-pot protocol.

Expanding the Tool Kit of Automated Flow Synthesis: Development of In-line Flash Chromatography Purification.

Recent advancements in in-line extraction and purification technology have enabled complex multistep synthesis in continuous flow reactor systems. However, for the large scope of chemical reactions that yield mixtures of products or residual starting materials, off-line purification is still required to isolate the desired compound. We present the in-line integration of a commercial automated flash chromatography system with a flow reactor for the continuous synthesis and isolation of product(s). A proof-of-principle study was performed to validate the system and test the durability of the column cartridges, performing an automated sequence of 100 runs over 2 days. Three diverse reaction systems that highlight the advantages of flow synthesis were successfully applied with in-line normal- or reversed-phase flash chromatography, continuously isolating products with 97-99% purity. Productivity of up to 9.9 mmol/h was achieved, isolating gram quantities of pure product from a feed of crude reaction mixture. Herein, we describe the development and optimization of the systems and suggest guidelines for selecting reactions well suited to in-line flash chromatography.

Synthesis of [211At]4-astato-L-phenylalanine by dihydroxyboryl-astatine substitution reaction in aqueous solution

Astatine-211 (211At)-labeled phenylalanine is expected to be a promising agent for targeted alpha-particle therapy for the treatment of patients with glioma. The existing reactions to prepare the labeled compound usually require organic solvents and metals that are toxic and hazardous to the environment. In this study, we developed a novel method wherein astatination was realized via the substitution of 211At for a dihydroxyboryl group coupled to phenylalanine. [211At]4-astato-L-phenylalanine was obtained as the carrier-free product in aqueous medium in high radiochemical yields (98.1 ± 1.9%, n = 5). The crude reaction mixture was purified by solid-phase extraction, and the radiochemical purity of the product was 99.3 ± 0.7% (n = 5). The high yield and purity were attributed to the formation of [211At]AtI and AtI2− as the reactive intermediates in the astatination reaction. The reaction did not require any organic solvents or toxic reagents, suggesting that this method is suitable for clinical applications.

GC/MSn analysis of the crude reaction mixtures from Friedel–Crafts acylation: Unambiguous identification and differentiation of 3‐aroylbenzofurans from their 4‐ and 6‐regioisomers

Rationale3‐Aroylbenzofurans and their 2‐nitrophenyl derivatives constitute fundamental intermediates for the synthesis of target compounds with pharmaceutical properties. However, their preparation via the Friedel–Crafts acylation of 2‐phenylbenzofurans, using Lewis acid as catalyst, often leads to mixtures of regioisomeric aroylbenzofurans that can be challenging to distinguish, thus preventing the reaction characterization.MethodWe report a method for the unambiguous identification and differentiation of the desired 3‐benzoyl isomers from their 4‐ and 6‐regioisomers in a crude reaction mixture using gas chromatography coupled to multiple‐stage mass spectrometric (GC/MSn) analysis performed in collision‐induced dissociation (CID) mode.ResultsUpon electron ionization, each set of isomers displayed nearly identical mass spectra. MSn revealed fragmentation patterns that varied in the location of the benzoyl group on the benzofuran scaffold: CID experiments performed on the molecular ion allowed the distinction of the 3‐acyl isomers from the 4‐ and 6‐regioisomers; CID experiments on the [M − Ar]+ ion allowed the distinction of the 4‐benzoyl from the 6‐benzoyl regioisomer, when the nitro group is located on the 2‐phenyl ring. Moreover, the unusual loss of OH• radical allowed ascertaining the position of the nitro group in 3‐acyl regioisomers bearing the NO2 group. The origin of the diagnostic OH• loss was investigated through MSn experiments using 18O‐labelled 3‐benzoyl derivatives.ConclusionsThe method allows the rapid characterization of crude reaction mixtures of benzoylbenzofurans using solely GC/MSn analysis, simplifying the workflow of extensive isolation and purification for structure elucidation.

Mechanochemistry as an Alternative Method of Green Synthesis of Silver Nanoparticles with Antibacterial Activity: A Comparative Study.

This study shows mechanochemical synthesis as an alternative method to the traditional green synthesis of silver nanoparticles in a comparative manner by comparing the products obtained using both methodologies and different characterization methods. As a silver precursor, the most commonly used silver nitrate was applied and the easily accessible lavender (Lavandula angustofolia L.) plant was used as a reducing agent. Both syntheses were performed using 7 different lavender:AgNO3 mass ratios. The synthesis time was limited to 8 and 15 min in the case of green and mechanochemical synthesis, respectively, although a significant amount of unreacted silver nitrate was detected in both crude reaction mixtures at low lavender:AgNO3 ratios. This finding is of particular interest mainly for green synthesis, as the potential presence of silver nitrate in the produced nanosuspension is often overlooked. Unreacted AgNO3 has been removed from the mechanochemically synthesized samples by washing. The nanocrystalline character of the products has been confirmed by both X-ray diffraction (Rietveld refinement) and transmission electron microscopy. The latter has shown bimodal size distribution with larger particles in tens of nanometers and the smaller ones below 10 nm in size. In the case of green synthesis, the used lavender:AgNO3 ratio was found to have a decisive role on the crystallite size. Silver chloride has been detected as a side-product, mainly at high lavender:AgNO3 ratios. Both products have shown a strong antibacterial activity, being higher in the case of green synthesis, but this can be ascribed to the presence of unreacted AgNO3. Thus, one-step mechanochemical synthesis (without the need to prepare extract and performing the synthesis as separate steps) can be applied as a sustainable alternative to the traditional green synthesis of Ag nanoparticles using plants.

N-p-Toluenesulfinylimidazole: A New in situ Reagent for the Mild and Efficient Synthesis of p-Toluenesulfinate Alkyl Esters and Aryl Esters

AbstractA new synthetic methodology has been developed for the synthesis of sulfinate alkyl and aryl esters. The methodology involves the combination of p-toluenesulfinic acid and 1,1′-carbonyldiimidazole (CDI) to create the putative reagent sulfinylimidazole. The process spontaneously releases carbon dioxide upon the addition of the CDI to the acid suggesting the rapid formation of the proposed reagent. Reaction of this reagent with a series of alcohols (primary, secondary, and tertiary) afforded the corresponding sulfinate alkyl esters in good to excellent yields by the addition of alcohols. It was also possible to form the related sulfinate aryl esters by treating the proposed sulfinylimidazole with selected phenols (phenol, p-tert-butylphenol, and thymol). The aryl esters were formed in excellent conversion based on analysis of the 500 MHz 1H NMR spectra of the crude reaction mixtures.

Metal-Organic Frameworks for Practical Separation of Cyclic and Linear Polymers.

The purification step in the manufacturing of cyclic polymers is difficult as complete fractionation to eliminate linear impurities requires considerable effort. Here, we report a new polymer separation methodology that uses metal-organic frameworks (MOFs) to discriminate between linear and cyclic polyethylene glycols (PEGs) via selective polymer insertion into the MOF nanopores. Preparation of a MOF-packed column allowed analytical and preparative chromatographic separation of these topologically distinct pairs. In addition, gram-scale PEGs with only cyclic structures were successfully obtained from a crude reaction mixture by using MOF as an adsorbent.

Metal‐Organic Frameworks for Practical Separation of Cyclic and Linear Polymers

AbstractThe purification step in the manufacturing of cyclic polymers is difficult as complete fractionation to eliminate linear impurities requires considerable effort. Here, we report a new polymer separation methodology that uses metal‐organic frameworks (MOFs) to discriminate between linear and cyclic polyethylene glycols (PEGs) via selective polymer insertion into the MOF nanopores. Preparation of a MOF‐packed column allowed analytical and preparative chromatographic separation of these topologically distinct pairs. In addition, gram‐scale PEGs with only cyclic structures were successfully obtained from a crude reaction mixture by using MOF as an adsorbent.

Synthesis and Structure of 5‐Diphenylphosphino‐ acenaphth‐6‐yl Boronic Acid, Related Dialkyl Esters and Boroxine Rings

AbstractThe reaction of 5‐Ph2P‐Ace‐6‐Li (prepared in situ from 6‐Ph2P‐Ace‐5‐Br and n‐BuLi in the presence of TMEDA) with B(OMe)3 and B(Oi‐Pr)3, respectively, provided the boronic esters 5‐Ph2P‐Ace‐6‐B(OR)2 (1 a, R=Me; 1 b, R=i‐Pr; Ace=acenaphthyl). Hydrolysis of the crude reaction mixture of 1 a, afforded the boronic acid 5‐Ph2P‐Ace‐6‐B(OH)2 (2), which crystallizes as hydrogen bonded complex 2 ⋅ TMEDA ⋅ CHCl3. Condensation of 2 yielded the related boroxine [5‐Ph2P‐Ace‐6‐BO]3 (3), which oxidized by air exclusively at one phosphorus atom to give the related boroxine [5‐Ph2P(O)‐Ace‐6‐BO(5‐Ph2P‐Ace‐6‐BO)2] (4). The new compounds have been analyzed by multinuclear NMR‐ and IR spectroscopy as well as X‐ray crystallography.

Four Different Crystalline Products from One Reaction: Unexpected Diversity of Products of the CuCl2 Reaction with N-(2-Pyridyl)thiourea

The reaction of N-(2-pyridyl)thiourea with CuCl2 in methanol yields four different crystalline products: yellow dimeric complex, [Cu2Cl2(μ-Cl)2(L)2] (1), red polymeric complex, [Cu3Cl8L2]n (2), orange crystalline product with ionic structure, L2[CuCl4] (3), and colourless ionic compound LCl (4), where L = 2-amino-[1,2,4]thiadiazolo[2,3-a]pyridin-4-ium cation as a result of oxidative cyclization of N-(2-pyridyl)thiourea. The crystal structures of all these crystalline products have been determined by single-crystal X-ray diffraction analysis. Compound 1 involves a copper(I) ion while in 2 and 3 the copper centre is in the divalent state. 1H NMR spectra for compounds 1–3 are identical and confirm deprotonated thioamide groups of N-(2-pyridyl)thiourea and the formation of a thiadiazolopyridinium cation in solution. The hydrogen bonding and π–π stacking interactions were investigated in the solid state. In addition, all crystalline products 1–4 exhibit also S···Cl bonding interactions which consolidate the complexes into networks. The X-ray diffraction analyses indicate the absence of other crystalline phases in the crude reaction mixture.

I+/TBHP Catalysis For Tandem Oxidative Cyclization To Indolo[2,3‐b]quinolines

AbstractWe report a chemoselective tandem oxidative cyclization/aromatization of indole derivatives tethered to aniline sulfonamides using catalytic amount of tetrabutylammonium iodide in the presence of tert‐butyl hydroperoxide (TBHP) as an oxidant under nearly neutral conditions at room temperature. The corresponding indolo[2,3‐b]quinolines were obtained as sulfonate salts, which could be easily isolated in analytically pure form via only a simple filtration of the crude reaction mixture. The natural product quinindoline could be easily obtained after basic work‐up of the sulfonate salt. Control experiments revealed that both ionic and radical active species could be generated in situ under mild conditions for the corresponding oxidative transformations to proceed in a chemoselective manner.

On the consensus nomenclature rules for radiopharmaceutical chemistry – Reconsideration of radiochemical conversion

Radiochemical conversion is an important term to be included in the “Consensus nomenclature rules for radiopharmaceutical chemistry”. Radiochemical conversion should be used to define reaction efficiency by measuring the transformation of components in a crude reaction mixture at a given time, whereas radiochemical yield is better suited to define the efficiency of an entire reaction process including, for example, separation, isolation, filtration, and formulation.

Achiral-Chiral Two-Dimensional Liquid Chromatography Platform to Support Automated High-Throughput Experimentation in the Field of Drug Development.

Automated high-throughput experimentation (HTE) is a powerful tool for scientists to explore and optimize chemical transformations by simultaneously screening yield, stereoselectivity, and impurity profiles. To analyze the HTE samples, high-throughput analysis (HTA) platforms must be fast, accurate, generic, and specific at the same time. A large amount of high-quality data is critical for the success of machine learning models in the era of big data. Conventional chiral liquid chromatography-mass spectrometry (LC/MS) HTE methods are hampered by compound co-eluting, possible ion suppression, and limited chiral column lifetime in the presence of crude reaction mixtures or complex sample matrices. To overcome these limitations, a generic and fast achiral-chiral heart-cutting two-dimensional (2D)-LC method has been developed to determine both the yield and stereoselectivity of chemical transformations within a 10 min run time. Successful implementation of the 2D-LC HTA platform in a routine drug development environment was achieved for real-world project support, with the analysis so far of over 2000 reaction mixtures prepared in the 96-well plate format. Excellent performance of the method was demonstrated by relative standard deviation (RSD) lower than 0.83% for the 1D and 2D retention times, and determination coefficients higher than 0.99. The presented HTA 2D-LC platform has had a significant impact on drug development by analyzing the HTE samples rapidly with unambiguous peak tracking and providing a robust approach for accurately generating a large amount of high-quality data in a short time.

No-additive salting-out liquid-liquid extraction-A tool for purification of positively charged compounds from highly salted reaction mixtures.

A novel and original application of salting-out assisted liquid-liquid extraction is presented. This technique was used to purify the final reaction products (quaternary ammonium salts) from unreacted components and by-products present in multiple excesses. The partition of two structurally related compounds as (2-aminoethyl)trimethylammonium salt (a labeling reagent) and a derivative of [2-(imidazoline-1-yl)ethyl]trimethylammonium salt (a final reaction product of N-acetylglucosamine labeling by (2-aminoethyl)trimethylammonium salt) between acetonitrile-rich and water-rich layers was monitored by hydrophilic interaction chromatography with electrospray ionization mass spectrometry. Despite the poor solubility of both highly polar substances in solutions containing a high concentration of acetonitrile, the main portion of the labeling reagent (72%) can be removed from the crude reaction mixture in the first extraction step using 95% acetonitrile/5% water as an extraction solvent. The purified final reaction product contained only 2% of the labeling reagent, and it was suitable for analysis by direct infusion mass spectrometry to confirm its identity. The capability of the suggested purification protocol to process small-volume highly salted reaction mixtures was also proven by analysis of saccharide mixture containing glucose, maltose, and maltotriose labeled by the positively charged tag.

Asymmetric Spirocyclization Enabled by Iridium and Brønsted Acid-Catalyzed Formal Reductive Cycloaddition

A catalytic, enantioselective spirocyclization of formanilides or formylindolines and enamides has been developed herein. The reaction proceeds through a sequential iridium-catalyzed hydrosilylatio...

Sunlight photolysis of cyclopentadienyl–tethered titanium(iv) permethyltitanocene chlorides

ABSTRACT Solutions of permethylcyclopentadienyl-tethered titanium(IV) chlorides incorporating one double bond in their tethers were exposed in glass vessels to sunlight, which triggered their photolytical reactions providing mixtures of products. Although the formation of several different products was apparent from 1H NMR spectra, only a single product could be identified in the crude reaction mixtures. This product was dicyclopentadiene [C10Me10], which arose from the recombination of the generally photodissociated C5Me5 radical. Amongst products that contained titanium, three complexes (3a, 3b and 4a) could be isolated after employing fractional crystallization and these complexes were characterized. The mechanism of 3a formation involves photodissociation of one η5-C5Me5 ligand from the parent complex, complemented by chlorine abstraction from another reactant molecule. Complexes 3b and 4a become formed via tether rearrangement, which starts with dissociating the tether Ti–C bond and is followed by rotating the tether, reattaching it subsequently through its available radical terminus.

A Practical Synthesis of [(tmeda)Ni(CH3)2], Isotopically Labeled [(tmeda)Ni(13CH3)2], and Neutral Chelated-Nickel Methyl Complexes

A practical procedure for the synthesis of N,N,N′,N′-tetramethylethylene diamine nickel dimethyl, [(tmeda)Ni(CH3)2] (5), based on commercially available methyllithium and [(tmeda)Ni(acac)2] (1) (acac = acetylacetonate), [(tmeda)Ni(OAc)2] (2) (OAc = acetate), [(tmeda)NiSO4] (3), or [(tmeda)NiF2] (4) has been developed. With 2 as the starting material, reproducible isolation of >14 g (ca. 68 mmol, 85%) of 5 in one-batch reactions is feasible. This synthetic route also enables the formation and isolation of 13C-labeled [(tmeda)Ni(13CH3)2] (5-13CH3) starting from 13CH3I by intermediate isolation of [(tmeda)2–3(Li13CH3)4]x (10). The amount of iodide impurities in 10 to push back iodide-catalyzed decomposition of 5-13CH3 to ethane and nickel black by a Kumada-type coupling is essential for successful isolation of 5-13CH3. [(tmeda)Ni(OAc)2] (2) is a superior nickel precursor to 5 in comparison to [(tmeda)Ni(acac)2] (1), as (a) removal of lithium acetate (9) from the crude reaction mixture is much easier than removal of lithium acetylacetonate and (b) κ2-N,O-salicylaldiminato nickel methyl complexes (12) or a κ2-P,O-phosphinesulfonato nickel methyl complex (14) can be easily prepared in a one-pot procedure starting from 2, methyllithium, and salicylaldimines (11) or phosphoniumsulfonate (13), respectively. The X-ray diffraction analyses of 2, 5, and 12b-PPh3 are reported.

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Solutions of permethylcyclopentadienyl-tethered titanium(IV) chlorides incorporating one double bond in their tethers were exposed in glass vessels to sunlight, which triggered their photolytical reactions providing mixtures of products. Although the formation of several different products was apparent from 1H NMR spectra, only a single product could be identified in the crude reaction mixtures. This product was dicyclopentadiene [C10Me10], which arose from the recombination of the generally photodissociated C5Me5 radical. Amongst products that contained titanium, three complexes (3a, 3b and 4a) could be isolated after employing fractional crystallization and these complexes were characterized. The mechanism of 3a formation involves photodissociation of one η5-C5Me5 ligand from the parent complex, complemented by chlorine abstraction from another reactant molecule. Complexes 3b and 4a become formed via tether rearrangement, which starts with dissociating the tether Ti–C bond and is followed by rotating the tether, reattaching it subsequently through its available radical terminus.

Selective Nuclear Magnetic Resonance Experiments for Sign-Sensitive Determination of Heteronuclear Couplings: Expanding the Analysis of Crude Reaction Mixtures.

State-of-the-art nuclear magnetic resonance (NMR) selective experiments are capable of directly analyzing crude reaction mixtures. A new experiment named HD-HAPPY-FESTA yields ultrahigh-resolution total correlation subspectra, which are suitable for sign-sensitive determination of heteronuclear couplings, as demonstrated here by measuring the sign and magnitude for proton–fluorine couplings (JHF) from major and minor isomer products of a two-step reaction without any purification. Proton–fluorine couplings ranging from 51.5 to −2.6 Hz could be measured using HD-HAPPY-FESTA, with the smallest measured magnitude of 0.8 Hz. Experimental JHF values were used to identify the two fluoroketone intermediates and the four fluoroalcohol products. Results were rationalized and compared with the density functional theory (DFT) calculations. Experimental data were further compared with the couplings reported in the literature, where pure samples were analyzed.