Ion Intermediates Research Articles

Preparation of functionalised heteropolyacid ionic liquids and their application in catalytic degradation of bottle-grade polyester

This research study is related to an environmentally friendly process method for catalytic degradation of bottle-grade PET by using ionic liquid catalysts.

Double Ring Expansion Strategy for Fused 3-Benzazepines: Alternative Synthesis of the Dolby-Weinreb Enamine.

A double ring expansion strategy for constructing fused 3-benzazepines is described. The oxidative ring expansion of spiroamine compounds with N-chlorosuccinimide and subsequent ring expansion of the resulting ketiminium ion intermediates with trimethylsilyldiazomethane afforded fused 3-benzazepines in a one-pot operation. Importantly, the Dolby-Weinreb enamine, which is a key synthetic intermediate for harringtonine alkaloids, cephalotaxines, can be accessed from commercial materials in only two steps using our developed method.

Prediction of High-Yielding Single-Step or Cascade Pericyclic Reactions for the Synthesis of Complex Synthetic Targets.

Pericyclic reactions, which involve cyclic concerted transition states without ionic or radical intermediates, have been extensively studied since their definition in the 1960s, and the famous Woodward-Hoffmann rules predict their stereoselectivity and chemoselectivity. Here, we describe the application of a fully automated reaction-path search method, that is, the artificial force induced reaction (AFIR), to trace an input compound back to reasonable starting materials through thermally allowed pericyclic reactions via product-based quantum-chemistry-aided retrosynthetic analysis (QCaRA) without using any a priori experimental knowledge. All categories of pericyclic reactions, including cycloadditions, ene reactions, group-transfer, cheletropic, electrocyclic, and sigmatropic reactions, were successfully traced back via concerted reaction pathways, and starting materials were computationally obtained with the correct stereochemistry. Furthermore, AFIR was used to predict whether the identified reaction pathway can be expected to occur in good yield relative to other possible reactions of the identified starting material. In order to showcase its practical utility, this state-of-the-art technology was also applied to the retrosynthetic analysis of a natural product with a relatively high number of atoms (52 atoms: endiandric acid C methyl ester), which was first synthesized by Nicolaou in 1982 and provided the corresponding starting polyenes with the correct stereospecificity via three pericyclic reaction cascades (one Diels-Alder reaction as well as 6π and 8π electrocyclic reactions). Moreover, not only systems that obey the Woodward-Hoffmann rules but also systems that violate these rules, such as those recently calculated by Houk, can be retrosynthesized accurately.

Effect of Solvents on 1-Butyl-1,2,4-Triazolium Trifluoroacetate Triggered Synthesis of 2,3-Dihydroquinazolin

Background: Quinazolinones are a class of heterocyclic compounds that have a wide variety of applications. They are also used in agrochemicals. There are several methodologies reported for the synthesis of 2,3-dihydroquinazolines using various catalysts. Method: Here, by using 1-butyl-1,2,4-triazolium as cation and trifluoroacetate as anion, 2,3-dihydroquinazolin-4(1H)-one has been synthesized. For the synthesis of 2,3-dihydroquinazolin-4(1H)-one condensation of anthranilamide with the corresponding aldehyde in the presence of organocatalyst and solvent is done. Using benzaldehyde as the parent aldehyde, to validate the outcome, the benzaldehydes were selected as follows a) benzaldehyde, b) 4-methoxybenzaldehyde – electron releasing group and c) 4-nitrobenzaldehyde – electronwithdrawing group. Solvent study has been done with solvents varied from polar to apolar. Both polar protic and polar aprotic solvents are used for the reactions. The polar protic solvents used were water, methanol, ethanol, isopropanol, butanol, hexane-1-ol, and glycerol. The polar aprotic solvents used are ethyl acetate, DMF,acetonitrile, and DMSO. The moderately apolar solvents used are DCM, carbon tetrachloride, 1,4 dioxane, and chloroform. Results: The synthesized triazolium salts are found soluble in polar aprotic, polar protic solvents and few moderately apolar solvents such as DCM, chloroform, acetonitrile, water, methanol and ethanol whereas insoluble with apolar solvents like toluene, benzene, and hexane.The yield of 2-phenyl-2,3-dihydroquinazolin-4(1H)-one was low for 1-butyl-1,2,4-triazolium trifluoroacetate based organocatalyst. But for substituted benzaldehyde, the yield was comparatively high. Comparatively, the yield for 2-(4-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one, where the aromatic benzaldehyde had electron-donating group, is less than 2-(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one, where the aromatic benzaldehyde had an electron-withdrawing group. Conclusion: Substituted benzaldehyde gave better yields than benzaldehyde. And nitro group which is electrowithdrawing attached to benzaldehyde enhanced the electrophilic nature at carbonyl center showed higher yields than methoxy group which is electron donating attached to benzaldehyde as it deactivates the carbonyl carbon. The polar protic solvents like water, ethanol and methanol stabilizes the ionic intermediates and gave better yield. Even the moderately apolar solvents like DCM, chloroform resulted in good yields, green solvents like water, ethanol and methanol would be a better choice as solvents. The carbon chain on the solvent has got an effect on product yield. As the carbon chain increases in solvent, the yield decreases due to the separation difficulties. The polar aprotic solvents did gave better yields but not as good as polar protic solvents.

Phenanthroline Catalysis in Stereoselective 1,2-cis Glycosylations.

The National Research Council's report in 2012 recognized glycosidic bond forming (glycosylation) reactions as critical due to the central importance of carbohydrates to the glycosciences. This report emphasized the need for the development of reproducible and broadly applicable glycosylation technologies to facilitate the stereoselective synthesis of biomedically relevant glycan libraries for tool development and for research applications by nonspecialists. In response to this report with NIH Common Fund support, the publications of new catalytic diastereoselective glycosylation protocols, some with broad generality under mild conditions, have been recently reported by our group and others. These recent discoveries have also advanced the understanding of the glycosylation reaction mechanism involving the coupling of a sugar electrophile bearing a leaving group at its C1-anomeric center with an alcohol nucleophile. This glycosidic bond forming reaction can lead to a mixture of two stereoisomers that differ in the configuration of the anomeric center.In our group, we discovered that readily available phenanthroline, a rigid and planar organic compound with two fused pyridine rings, could be utilized as a nucleophilic catalyst to promote highly diastereoselective glycosylation of an alcohol nucleophile with a sugar bromide electrophile. The phenanthroline catalysis process allows access to a myriad of high yielding and diastereoselective 1,2-cis pyranosides and furanosides. This catalyst-controlled approach has been applied to the synthesis of a potential vaccine adjuvant α-glucan octasaccharide. For pyranosyl bromide electrophiles, an extensive mechanistic investigation illustrated that two phenanthrolinium ion intermediates, a 4C1 chair-liked equatorial-conformer and a B2,5 boat-like axial-conformer, are formed in a ratio of 2:1 (equatorial/axial). To obtain high levels of axial-1,2-cis selectivity, a Curtin-Hammett scenario was proposed wherein interconversion of the 4C1 equatorial-conformer and B2,5 axial-conformer is more rapid than nucleophilic addition. Hydroxyl attack takes place from the axial-face of the more reactive 4C1 chairlike equatorial intermediate to afford an axial-1,2-cis glycoside product. The phenanthroline catalysis system is applicable to a number of furanosyl bromide electrophiles to provide the challenging 1,2-cis substitution products in good yield and diastereoselectivity. NMR experiments and density-functional theory (DFT) calculations support an associative mechanism in which the rate-determining step takes place from an invertive displacement of the faster reacting furanosyl phenanthrolinium ion intermediate with an alcohol nucleophile. Overall, this work stands at the underdeveloped intersection of operationally simple conditions, catalysis, and stereocontrolled glycosidic bond formation, each of which represents an important theme in the preparation of biologically important oligosaccharides and glycopeptides for applications to human health and medicine.

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients.

The detection of N-nitrosamines, derived from solvents and reagents and, on occasion, the active pharmaceutical ingredient (API) at higher than acceptable levels in drug products, has led regulators to request a detailed review for their presence in all medicinal products. In the absence of rodent carcinogenicity data for novel N-nitrosamines derived from amine-containing APIs, a conservative class limit of 18 ng/day (based on the most carcinogenic N-nitrosamines) or the derivation of acceptable intakes (AIs) using structurally related surrogates with robust rodent carcinogenicity data is recommended. The guidance has implications for the pharmaceutical industry given the vast number of marketed amine-containing drugs. In this perspective, the rate-limiting step in N-nitrosamine carcinogenicity, involving cytochrome P450-mediated α-carbon hydroxylation to yield DNA-reactive diazonium or carbonium ion intermediates, is discussed with reference to the selection of read-across analogs to derive AIs. Risk-mitigation strategies for managing putative N-nitrosamines in the preclinical discovery setting are also presented.

Perspective on Radiolytic Charging for Redox Flow Battery Electrolytes Using the Nuclear Decay Energy of Spent Nuclear Fuel/Radionuclides

The conversion of nuclear energy into electricity is facilitated by chemical intermediates and molecular products formed during the radiolysis of water. In this work, we hypothesize a novel radiolytic charging approach for redox flow battery electrolytes. Radiolytically produced ionic intermediates and molecular products oxidize or reduce the metal ion solutes in the electrolytes. A qualitative study for choice of redox couples based on electrochemical principles followed by a feasibility study of radiolytic conversion of active material is presented. A framework for an empirical investigation of radioactive source, equipment and dose, and product characterization techniques is discussed. The proposed method finds application in the utilization of spent nuclear fuel (specifically gamma emissions from fission products in early activity stages) as a radiolysis radiation source for electrolyte charging. We present a perspective on future investigations that are required to harness nuclear energy for charging electrolytes and developing a self-operating RFB system.

Oxoammonium Salt-Promoted Multifunctionalization of Saturated Cyclic Amines Based On β-Oxo Cyclic Iminium Ion Intermediates.

Herein we describe a convenient method for multiple C(sp3)-H bond functionalization of saturated cyclic amines through oxoammonium salt-promoted oxidation to afford a β-oxo cyclic iminium ion as a key intermediate, followed by cascade addition with thiocyanate and diverse N-, O-, and S-containing nucleophiles in the green solvent and EtOH. Notably, chiral spiro azapolyheterocycles were prepared enantioselectively (>20:1 dr, up to 99% ee) when cysteine or serine esters were used as substrates. Moreover, the concise late-stage modification of several natural product derivatives was accomplished using this method.

A Tandem Prins/Friedel‐Crafts Cyclization Strategy for the Stereoselective Synthesis of Hexahydro‐2H‐benzo[g]chromenes

AbstractA tandem Prins/Friedel‐Crafts cascade strategy has been developed for the synthesis of hexahydro‐2H‐benzo[g]chromene derivatives. Under action of equimolecular amount of BF3 etherate, δ,ϵ‐unsaturated alcohols and arylacetaldehydes are coupled to form oxocarbenium ion intermediates, which are captured by the alkene moiety through a favored six‐membered transition state. The Prins‐cyclization resultant tertiary carbenium ions undergo consecutive intramolecular Friedel–Crafts cyclization to create the tricyclic products. This process enables a tandem formation of three new chemical bonds in one single operation with high yields and stereoselectivity in most cases. When cyclic substituents are involved, a variety of spiro derivatives could also be synthesized successfully, which further proved the robustness of this methodology.

Chiral Chalcogenide-Catalyzed Enantioselective Electrophilic Hydrothiolation of Alkenes.

A new strategy for the construction of chiral sulfides by catalytic enantioselective hydrothiolation of alkenes via an electrophilic pathway has been developed. Using this strategy, cyclic and acyclic unactivated alkenes efficiently afforded various chiral products in the presence of electrophilic sulfur reagents and silanes through chiral chalcogenide catalysis. The obtained products were easily transformed into other types of valuable chiral sulfur-containing compounds. Mechanistic studies revealed that the superior construction of chiral thiiranium ion intermediate is the key to achieving such a transformation.

Exploiting photoredox catalysis for carbohydrate modification through C-H and C-C bond activation.

Photoredox catalysis has recently emerged as a powerful synthetic platform for accessing complex chemical structures through non-traditional bond disconnection strategies that proceed through free-radical intermediates. Such synthetic strategies have been used for a range of organic transformations; however, in carbohydrate chemistry they have primarily been applied to the generation of oxocarbenium ion intermediates in the ubiquitous glycosylation reaction. In this Review, we present more intricate light-induced synthetic strategies to modify native carbohydrates through homolytic C-H and C-C bond cleavage. These strategies allow access to glycans and glycoconjugates with profoundly altered carbohydrate skeletons, which are challenging to obtain through conventional synthetic means. Carbohydrate derivatives with such structural motifs represent a broad class of natural products integral to numerous biochemical processes and can be found in active pharmaceutical substances. Here we present progress made in C-H and C-C bond activation of carbohydrates through photoredox catalysis, focusing on the operational mechanisms and the scope of the described methodologies.

Low-temperature mineralization of perfluorocarboxylic acids.

Per- and polyfluoroalkyl substances (PFAS) are persistent, bioaccumulative pollutants found in water resources at concentrations harmful to human health. Whereas current PFAS destruction strategies use nonselective destruction mechanisms, we found that perfluoroalkyl carboxylic acids (PFCAs) could be mineralized through a sodium hydroxide-mediated defluorination pathway. PFCA decarboxylation in polar aprotic solvents produced reactive perfluoroalkyl ion intermediates that degraded to fluoride ions (78 to ~100%) within 24 hours. The carbon-containing intermediates and products were inconsistent with oft-proposed one-carbon-chain shortening mechanisms, and we instead computationally identified pathways consistent with many experiments. Degradation was also observed for branched perfluoroalkyl ether carboxylic acids and might be extended to degrade other PFAS classes as methods to activate their polar headgroups are identified.

Caught while Dissolving: Revealing the Interfacial Solvation of the Mg2+ Ions on the MgO Surface.

Interfaces between water and materials are ubiquitous and are crucial in materials sciences and in biology, where investigating the interaction of water with the surface under ambient conditions is key to shedding light on the main processes occurring at the interface. Magnesium oxide is a popular model system to study the metal oxide–water interface, where, for sufficient water loadings, theoretical models have suggested that reconstructed surfaces involving hydrated Mg2+ metal ions may be energetically favored. In this work, by combining experimental and theoretical surface-selective ambient pressure X-ray absorption spectroscopy with multivariate curve resolution and molecular dynamics, we evidence in real time the occurrence of Mg2+ solvation at the interphase between MgO and solvating media such as water and methanol (MeOH). Further, we show that the Mg2+ surface ions undergo a reversible solvation process, we prove the dissolution/redeposition of the Mg2+ ions belonging to the MgO surface, and we demonstrate the formation of octahedral [Mg(H2O)6]2+ and [Mg(MeOH)6]2+ intermediate solvated species. The unique surface, electronic, and structural sensitivity of the developed technique may be beneficial to access often elusive properties of low-Z metal ion intermediates involved in interfacial processes of chemical and biological interest.

Highly Regio- and Stereoselective Intramolecular Rearrangement of Glycidol Acetal to Alkoxy Cyclic Acetals.

A new class of highly regio- and stereoselective intramolecular rearrangements of glycidol acetals to produce alkoxylated 1,3-dioxolane/1,3-dioxane is demonstrated. Selective Lewis acid activation of acetal generates an oxocarbenium ion that initiates the epoxide ring-opening event, giving the bicyclic [3,1,0]epoxonium ion intermediate that undergoes exo/endo-selective opening by a tethered alkoxide. Mechanistic insights into preferential acetal activation over the epoxide were obtained by crossover experiments. The method was applied in the total synthesis of parvistone B and its 8-ethoxy analogue.

Front Cover: α‐Aziridinyl Carbenium Ion Intermediate and Stereoselective Dehydroxylative Diarylation of Aziridin‐2‐yl Carboxaldehyde (Asian J. Org. Chem. 7/2022)

α-Aziridinyl carbenium ion as an intermediate was observed for the first time from the reaction of aziridin-2-yl arylmethanol with Lewis acid BF3⋅OEt2. This intermediate was further reacted with various nucleophiles to afford the adducts in highly stereoselective manner as single-isomer molecules. α-Aziridinyl carbenium ion intermediate was observed spectroscopically as a crucial intermediate, and density functional theory (DFT) calculations show the origin of stereoselectivity based on thermodynamic preference for the reaction. More information can be found in the Research Article by Hyun-Joon Ha, and Hyunwoo Kim et al.

α‐Aziridinyl Carbenium Ion Intermediate and Stereoselective Dehydroxylative Diarylation of Aziridin‐2‐yl Carboxaldehyde

Abstractα‐Aziridinyl carbenium ion as an intermediate was observed for the first time from the reaction of aziridin‐2‐yl arylmethanol with Lewis acid BF3 ⋅ OEt2. This intermediate was further reacted with various nucleophiles including electron‐rich arenes to afford the adducts in highly stereoselective manner as singly isomers. α‐Aziridinyl carbenium ion intermediate was observed spectroscopically as a crucial intermediate, and density functional theory (DFT) calculations show the origin of stereoselectivity based on thermodynamic preference for the reaction.

Transition metal-free cross-coupling reactions to form carbon–heteroatom bonds

The formation of carbon–heteroatm bond is the key step of synthesis of numerous organic compounds, including socially important products such as pharmaceuticals, crop protection agents and organic functional materials. These reactions proceed most efficiently when catalyzed by compounds of transition metals, first of all palladium. However, this approach has considerable drawbacks, in particular, high cost and toxicity of transition metal compounds and harsh reaction conditions required in some cases, resulting in limited functional group tolerance. This review describes the recent advances in the development of methodology of transition metal-free carbon–heteroatom bond-forming cross-coupling. It is shown that single-electron transfer and homolytic bond cleavage result in the generation of highly reactive radical and/or radical ion intermediates, enable the formation of new carbon–heteroatom bonds. These intermediates are generated using either visible light or electricity as energy sources or simple organic compounds acting as electron donors. Methods for carbon–heteroatom bond formation based on radical reactions proceeding under mild conditions and in the presence of labile functional groups are considered. The key mechanistic aspects of the reactions are highlighted. The review mainly covers the original publications of the current decade.The bibliography includes 302 references.

Characterization of Elusive Reaction Intermediates Using Infrared Ion Spectroscopy: Application to the Experimental Characterization of Glycosyl Cations.

ConspectusA detailed understanding of the reaction mechanism(s) leading to stereoselective product formation is crucial to understanding and predicting product formation and driving the development of new synthetic methodology. One way to improve our understanding of reaction mechanisms is to characterize the reaction intermediates involved in product formation. Because these intermediates are reactive, they are often unstable and therefore difficult to characterize using experimental techniques. For example, glycosylation reactions are critical steps in the chemical synthesis of oligosaccharides and need to be stereoselective to provide the desired α- or β-diastereomer. It remains challenging to predict and control the stereochemical outcome of glycosylation reactions, and their reaction mechanisms remain a hotly debated topic. In most cases, glycosylation reactions take place via reaction mechanisms in the continuum between SN1- and SN2-like pathways. SN2-like pathways proceeding via the displacement of a contact ion pair are relatively well understood because the reaction intermediates involved can be characterized by low-temperature NMR spectroscopy. In contrast, the SN1-like pathways proceeding via the solvent-separated ion pair, also known as the glycosyl cation, are poorly understood. SN1-like pathways are more challenging to investigate because the glycosyl cation intermediates involved are highly reactive. The highly reactive nature of glycosyl cations complicates their characterization because they have a short lifetime and rapidly equilibrate with the corresponding contact ion pair. To overcome this hurdle and enable the study of glycosyl cation stability and structure, they can be generated in a mass spectrometer in the absence of a solvent and counterion in the gas phase. The ease of formation, stability, and fragmentation of glycosyl cations have been studied using mass spectrometry (MS). However, MS alone provides little information about the structure of glycosyl cations. By combining mass spectrometry (MS) with infrared ion spectroscopy (IRIS), the determination of the gas-phase structures of glycosyl cations has been achieved. IRIS enables the recording of gas-phase infrared spectra of glycosyl cations, which can be assigned by matching to reference spectra predicted from quantum chemically calculated vibrational spectra. Here, we review the experimental setups that enable IRIS of glycosyl cations and discuss the various glycosyl cations that have been characterized to date. The structure of glycosyl cations depends on the relative configuration and structure of the monosaccharide substituents, which can influence the structure through both steric and electronic effects. The scope and relevance of gas-phase glycosyl cation structures in relation to their corresponding condensed-phase structures are also discussed. We expect that the workflow reviewed here to study glycosyl cation structure and reactivity can be extended to many other reaction types involving difficult-to-characterize ionic intermediates.

Direct and Sequential Bioactivation of Pemigatinib to a Reactive Iminium Ion Intermediate Culminates in Mechanism‐Based Inactivation of Cytochrome P450 3A

Mechanism‐based inactivation (MBI) is a unique phenomenon in drug metabolism that arises when an enzyme metabolically activates a drug to a chemically reactive intermediate and primes it for irreversible binding, leading to an irrevocable loss of catalytic activity that is only restored upon de novo synthesis of the implicated enzyme. Our laboratory recently established the MBI of cytochrome P450 3A (CYP3A) by the fibroblast growth factor receptor (FGFR) inhibitors erdafitinib and infigratinib. Serendipitously, our preliminary data has also revealed that pemigatinib (PEM) – another clinically approved FGFR1‐3 inhibitor – similarly elicited time‐dependent inhibition of CYP3A. This was rather unexpected as it was previously purported that PEM did not pose any metabolism‐dependent liabilities due to the absence of glutathione‐related conjugates in metabolic profiling experiments conducted in human liver microsomes. Consequently, we posited that PEM is bioactivated by CYP3A to a hard electrophile, thereby allowing it to elude glutathione trapping and detection in the aforementioned reactive metabolite screen. Here, we confirmed that PEM inhibited both CYP3A isoforms in a time‐, concentration‐, and cofactor‐dependent manner consistent with MBI – with KI, kinact, and partition ratio of 8.69 and 11.95 μM, 0.108 and 0.042 min−1, and ~44 and ~47 for CYP3A4 and CYP3A5 respectively, when rivaroxaban was employed as the probe substrate. While the rate of inactivation was diminished by coincubation with an alternative substrate (testosterone) or direct inhibitor of CYP3A (ketoconazole), the inclusion of nucleophilic trapping agents afforded no such protection. Furthermore, the lack of catalytic activity recovery following dialysis and oxidation with potassium ferricyanide coupled with the absence of a spectrally resolvable peak in the Soret region collectively implied that the underlying mechanism of inactivation was not elicited via the formation of pseudoirreversible metabolite‐intermediate complexes. Utilizing cyanide trapping and high‐resolution mass spectrometry, we illuminated the direct and sequential oxidative bioactivation of PEM and its major O‐desmethylated metabolite at its distal morpholine moiety to a reactive iminium ion intermediate that could covalently modify the CYP3A apoprotein and/or prosthetic heme and culminate in its MBI. Finally, structural determinants gleaned from our in silicocovalent docking simulations suggested that the discrepancies in MBI potencies between both CYP3A isoforms might be alluded to the propensity for PEM to interact more favourably with an accessible active‐site serine residue in position 312 of CYP3A4 as compared to CYP3A5. Further physiologically based pharmacokinetic modelling studies are currently underway to better discern the clinical implications of our findings.

Diastereoselective Substitution Reactions of Acyclic β-Alkoxy Acetals via Electrostatically Stabilized Oxocarbenium Ion Intermediates.

Substitution reactions of acyclic β-alkoxy acetals proceeded with generally high diastereoselectivities (>90:10) to form the anti product. Mechanistic experiments supplemented with computational studies suggest that, upon activation of the acetal, the resulting oxocarbenium ion is electrostatically stabilized by the β-alkoxy group. This stabilization defines the conformation of the reactive intermediate, which can be attacked preferentially from the more exposed face, leading to the observed products.