Ring Intermediates Research Articles

Olefination with sulfonyl halides and esters: Mechanistic DFT and experimental studies, and comparison with reactivity of phosphonates

Olefination of carbonyl compounds with carbanions of sulfonyl halides and activated sulfonates runs via aldol-type addition, cyclization to four-membered ring intermediates, and fragmentation to alkenes. The sequence differs from mechanism of sulfur-based Julia and (one-pot) Julia-Kocienski reactions, and mimics behavior of phosphorus-based reagents. In our report, we present energetic profile of the process based on DFT calculations, and discuss factors, which control E/Z-selectivity of produced alkenes. Importantly, the calculations reveal that the fragmentation step displays the highest barrier and involves anti-apicophilic oxathietanes, in which the OCH2CF3 group is located on the opposite side to the carbon atom. Aldehyde-exchange experiments, designed to keep steric constrains virtually unchanged, reveal effect of carbanion nucleophilicity on equilibration of the aldol addition step. We also demonstrate synthesis of non-stabilized and semi-stabilized carbanion precursors: octane- and phenylmethane-phosphonates of fluorinated alcohols (TFE and HFIP), and probe their reactions with benzaldehyde.

Two P, Ten P, White P, Red P: Mechanistic Exploration of the Oligomerization of Red Phosphorus from Diphosphorus with the Ab Initio Nanoreactor.

Phosphorus is critical to humans on many fronts, yet we do not have a mechanistic understanding of some of its most basic transformations and reactions─namely the oligomerization of white phosphorus to red. With heat or under ultraviolet (UV) exposure, it has been experimentally demonstrated that white phosphorus dissociates into diphosphorus units which readily form red phosphorus. However, the mechanism of this process is unknown. The ab initio nanoreactor approach was used to explore the potential energy surface of phosphorus clusters. Density functional theory and metadynamics simulations were used to characterize potential reaction pathways. A mechanism for oligomerization is proposed to take place via diphosphorus additions at π-bonds and weak σ-bonds through three membered ring intermediates. Downhill paths through P6 and P8 clusters eventually result in P10 clusters that can oligomerize into red phosphorus chains. The initial, rate limiting step for this process has an energy barrier of 24.2 kcal/mol.

Halogenation of Alkenes Using Three‐Component Reactions: A Decade of Development

AbstractAlkenes are valuable feedstocks in organic synthesis. One effective method for synthesizing organic halides with functional groups in close proximity involves the direct difunctionalization of alkenes via three‐component reactions. This approach not only reduces the number of steps involved in the synthesis process, but also minimizes waste generation and enables the formation of complex molecules from simple starting materials. In this review, we mainly discuss decade developments (2013‐2023) in two categories: (1) halogenation via three‐membered ring intermediates, involving haliranium, thiiranium,seleniranium, aziridinium and epoxide species; (2) halogenation via a radical pathway. Reactions with I2, BiI3, NaI, Bu4N+[I(O2CAr)2]−, NIS, NBS, NCS, DBH, BsNMeBr, HBr, HCl, KI, NH4I, I2O5, Et3N ⋅ 3HF, Selectfluor, CuI, CuBr, CuCl, LiCl, KBr, NaCl, SOCl2, Py ⋅ 9HF, NFSI, TBSCl et al have been recorded and how the added reagents work will be discussed. We hope this review will do help for future research in this area.

Three‐Component Reactions of Alkenes with C−C Bond Formation: Recent Developments

AbstractAlkenes are highly valuable materials in organic synthesis, and their three‐component reactions offer a promising method for C−C bond formation and carbon chain elongation. This approach not only reduces the number of reaction steps but also minimizes waste generation, enabling the preparation of polysubstituted alkanes from simple starting materials. In this review, we provide an overview of recent advancements in this field from 2013 to 2023. We have classified the developments into three main categories: (1) reactions triggered by C‐radicals or heteroatom‐radicals; (2) cascades involving three‐membered ring intermediates; and (3) transformations catalyzed by metals. We will discuss a wide range of reactions that involve diazoium salts, arylhydrazines, acids, aldehydes, 1,3‐dicarbonyls, diazo compounds, amines, malononitriles, diacyl peroxides, ethers, 1,3‐dithiane, arenes, CuSCF3, selectfluor, Et3N ⋅ 3HF, TBHP, CH2Cl2, CHCl3, CO2, CO, KCl, H2O, and other reagents. These reactions lead to alkylation, arylation, or carbonylation products. We believe that this review will be helpful for future research in this area.

Are β-Lactones Involved in Carbon-Based Olefination Reactions?

AbstractHeteroatom-based olefinating reagents (e.g., organic phosphonates, sulfonates, etc.) are used to transform carbonyl compounds into alkenes, and their mechanism of action involves aldol-type addition, cyclization, and fragmentation of four-membered ring intermediates. We have developed an analogous process using ethyl 1,1,1,3,3,3-hexafluoroisopropyl methylmalonate, which converts electrophilic aryl aldehydes into α-methylcinnamates in up to 70% yield. The reaction plausibly proceeds through the formation of β-lactone that spontaneously decarboxylates under the reaction conditions. The results shed light on the Knoevenagel–Doebner olefination, for which decarboxylative anti-fragmentation of aldol-type adducts is usually considered.

Density-functional tight-binding molecular dynamics study on fixation reaction of CO2 to styrene oxide catalyzed by Mg-MOF-74 metal-organic framework

Abstract Carbon capture and utilization is a strategy to reduce CO2 emissions by utilizing them to synthesize fine chemicals. Mg-MOF-74 exhibits exceptional CO2 adsorption capacity and functions as a catalyst in styrene carbonate synthesis from CO2 and styrene oxide. We examined the structural properties and energetics of styrene carbonate synthesis in Mg-MOF-74 at the third-order density-functional tight-binding level. A novel reaction mechanism via the formation of a seven-membered ring intermediate was found to exhibit a lower Gibbs activation energy than the previously proposed mechanism.

Study on the Mechanism of Ru-Catalyzed Cyclization of Aromatic Amides with Allylphosphine Oxides.

The mechanism of Ru-catalyzed cyclization of aromatic amides with allylphosphine oxides is studied by density functional theory calculation (DFT). The results show that, first, a 5-membered Ru ring intermediate is formed by N-H and C-H diprotons via the concerted metalation-deprotonation mechanism (CMD) and then the allylphosphine oxide is inserted through the ring-extending reaction to form a 7-membered ring intermediate. Next, reduction elimination is followed via intramolecular hydrogen transfer isomerization. At last, with the assistance of acetic acid, Ru (II) → Ru (IV) → Ru (II) complexes occur from the 7-membered Ru ring intermediate, and the final product is formed by reduction elimination and protonation reaction, while the catalyst is released to participate in the next cycle.

Access to N-Alkylazaheterocyclic Salts by Activation of Alkoxy C-O Bonds in Polyol Esters.

A wide variety of N-alkylazaheterocyclic salts are conveniently synthesized from polyol esters and azaheterocyclic salts under solventless conditions. In particular, paraquat-like derivatives showed comparable herbicidal activity toward several common weeds. Mechanistic studies suggest that polyesters likely underwent partial hydrolysis and neighboring group participating dehydration under the action of acidic salt to generate five-membered ring intermediates, which reacted with the azaheterocycle to accomplish the N-alkylation.

Enzyme-independent catabolism of cysteine with pyridoxal-5′-phosphate

Pyridoxal-5′-phosphate (PLP) is a versatile cofactor that assists in different types of enzymatic reactions. PLP has also been reported to react with substrates and catalyze some of these reactions independent of enzymes. One such catalytic reaction is the breakdown of cysteine to produce hydrogen sulfide (H2S) in the presence of multivalent metal ions. However, the enzyme-independent catalytic activity of PLP in catabolizing cysteine in the absence of multivalent ions is unknown. In this study, we show that PLP reacts with cysteine to form a thiazolidine product, which is supported by quantum chemical calculations of the absorption spectrum. The reaction of PLP with cysteine is dependent on ionic strength and pH. The thiazolidine product slowly decomposes to produce H2S and the PLP regenerates to its active form with longer reaction times (> 24 h), suggesting that PLP can act as a catalyst. We propose an enzyme-independent plausible reaction mechanism for PLP catalyzed cysteine breakdown to produce H2S, which proceeds through the formation of thiazolidine ring intermediates that later hydrolyzes slowly to regenerate the PLP. This work demonstrates that PLP catalyzes cysteine breakdown in the absence of enzymes, base, and multivalent metal ions to produce H2S.

Photodissociation of quinoline cation: Mapping the potential energy surface.

A detailed exploration of the potential energy surface of quinoline cation (C9H7N·+) is carried out to extend the present understanding of its fragmentation mechanisms. Density functional theory calculations have been performed to explore new fragmentation schemes, giving special attention to previously unexplored pathways, such as isomerization and elimination of HNC. The isomerization mechanisms producing five- to seven-membered ring intermediates are described and are found to be a dominant channel both energetically and kinetically. Energetically competing pathways are established for the astrochemically important HNC-loss channel, which has hitherto never been considered in the context of the loss of a 27amu fragment from the parent ions. Elimination of acetylene was also studied in great detail. Overall, the computational results are found to complement the experimental observations from the concurrently conducted PEPICO investigation. These could potentially open the doors for rich and interesting vacuum ultraviolet radiation-driven chemistry on planetary atmospheres, meteorites, and comets.

Reprocessing of Covalent Adaptable Polyamide Networks through Internal Catalysis and Ring-Size Effects.

Here, we report the introduction of internally catalyzed amide bonds to obtain covalent adaptable polyamide networks that rely on the dissociation equilibrium between dicarboxamides and imides. While amide bonds are usually considered to be robust and thermally stable, the present study shows that their dynamic character can be activated by a smart choice of available building blocks without the addition of any external catalyst or other additives. Hence, a range of polyamide-based dynamic networks with variable mechanical and viscoelastic properties have been obtained in a systematic study, using a straightforward curing process of dibasic ester and amine compounds. Since the dissociation process involves a cyclic imide formation, the correlation between ring size and the thermomechanical viscosity profile was studied for five- to seven-membered ring intermediates, depending on the chosen dibasic ester monomer. This resulted in a marked temperature response with activation energies in the range of 116-197 kJ mol-1, yielding a sharp transition between elastic and viscous behavior. Moreover, the ease and versatility of this chemistry platform were demonstrated by selecting a variety of amines, resulting in densely cross-linked dynamic networks with Tg values ranging from -20 to 110 °C. With this approach, it is possible to design amorphous polyamide networks with an acute temperature response, allowing for good reprocessability and, simultaneously, high resistance to irreversible deformation at elevated temperatures.

Mechanism of the Kinugasa Reaction Revisited.

The mechanism of the Kinugasa reaction, that is, the copper-catalyzed formation of β-lactams from nitrones and terminal alkynes, is re-evaluated by means of density functional theory calculations and in light of recent experimental findings. Different possible mechanistic scenarios are investigated using phenanthroline as a ligand and triethylamine as a base. The calculations confirm that after an initial two-step cycloaddition promoted by two copper ions, the resulting five-membered ring intermediate can undergo a fast and irreversible cycloreversion to generate an imine and a dicopper-ketenyl intermediate. From there, the reaction can proceed through a nucleophilic attack of a ketenyl copper intermediate on the imine and an intramolecular cyclization, rather than through the previously suggested (2 + 2) Staudinger synthesis.

Efficient and scalable methods for synthesis of midazolam drug with an annulation process

The reported methods for the synthesis of midazolam include a number of disadvantages, such as high production cost and low yields. The purpose of this investigation was to develop a more economical and technically more feasible route to synthesis of midazolam. In this research, two easy and scalable synthetic methods for the production of midazolam drug are presented. One-pot condensation of imidoyl chloride or 1,4-benzodiazepinic N-nitrosoamidines with carbanion of two isocyanide reagents is described and two important and key tricyclic ring intermediates synthesized. These imidazo-type structures can be derivatives by the alkylation of the imidazole ring with tert-butyl magnesium chloride at 0 °C in excellent yield, which have not been described for these intermediates in the literatures.

Impact of Organic Templates on the Selective Formation of Zeolite Oligomers

AbstractZeolites are essential materials to industry due to their adsorption and catalytic properties. The best current approach to prepare a targeted zeolite still relies on trial and error's synthetic procedures since a rational understanding of the impact of synthesis variables on the final structures is still missing. To discern the role of a variety of organic templates, we perform simulations of the early stages of condensation of silica oligomers by combining DFT, Brønsted‐Evans‐Polanyi relationships and kinetic Monte Carlo simulations. We investigate an extended reaction path mechanism including 258 equilibrium reactions and 242 chemical species up to silica octamers, comparing the computed concentrations of Si oligomers with 29SI NMR experimental data. The effect of the templating agent is linked to the modification of the intramolecular H‐bond network in the growing oligomer, which produces higher concentration of 4‐membered ring intermediates, precursors of the key double‐four ring building blocks present on more than 39 known zeolite topologies.

Impact of Organic Templates on the Selective Formation of Zeolite Oligomers.

Zeolites are essential materials to industry due to their adsorption and catalytic properties. The best current approach to prepare a targeted zeolite still relies on trial and error's synthetic procedures since a rational understanding of the impact of synthesis variables on the final structures is still missing. To discern the role of a variety of organic templates, we perform simulations of the early stages of condensation of silica oligomers by combining DFT, Brønsted-Evans-Polanyi relationships and kinetic Monte Carlo simulations. We investigate an extended reaction path mechanism including 258 equilibrium reactions and 242 chemical species up to silica octamers, comparing the computed concentrations of Si oligomers with 29 SI NMR experimental data. The effect of the templating agent is linked to the modification of the intramolecular H-bond network in the growing oligomer, which produces higher concentration of 4-membered ring intermediates, precursors of the key double-four ring building blocks present on more than 39 known zeolite topologies.

Combining Chemical and Biological Oxidation for Sustainable Treatment of Chloronitrobenzene in Anoxic Groundwater

AbstractChloronitrobenzenes (CNBs) are important chemical intermediates that are resistant to natural degradation processes in anoxic environments. When receptors are threatened by CNB‐contaminated groundwater, advanced oxidation processes (AOPs) offer a rapid response to protect human health and the environment. While AOPs are effective for the transformation of persistent organic contaminants, driving chemical oxidation reactions to complete mineralization is often not energy‐ and cost‐efficient due to the formation of recalcitrant intermediates or competition by natural organic matter. In this study, we applied an electrochemical AOP to elucidate the degradation pathways and kinetics of CNB under varying treatment conditions and times. Nontargeted mass spectrometry revealed multiple ring hydroxylation and ring opening products such as dicarboxylic acids that became increasingly harder to chemically oxidize as treatment time progressed. To determine the universal biodegradability of the generated intermediates under anoxic conditions, AOP‐treated water samples collected at different stages of electrochemical oxidation were exposed to a microbial culture derived from generic rhizosphere soil. All ring opening products were completely biodegraded anaerobically within 28 days of microcosm incubation. While multiple oxygenated ring intermediates were substantially removed, CNB was stable in the absence of oxygen. Our findings demonstrate that the combination of limited and targeted chemical oxidation with subsequent biodegradation of incomplete oxidation products is a more sustainable approach than the exclusive application of AOPs for the treatment of groundwater contaminated with CNBs and likely other aromatic compounds.

An Unconventional trans - exo -Selective Cyclization of Alkyne-Tethered Cyclohexadienones Initiated by Rhodium(III)-Catalyzed C–H Activation via Insertion Relay

Different from the established trans-endo-selective cyclization of alkyne-tethered electrophiles that involve an E/Z isomerization process, herein, the authors present a novel strategy to allow tra...

Catalytic wet air oxidation of phenol by cordierite honeycomb washcoated with Al/Zr pillared bentonite in a plug flow reactor

Cordierite monoliths coated with Al/Zr pillared bentonite clay powder were synthesized and tested for catalytic wet air oxidation (CWAO) of phenol aqueous solutions in a plug flow reactor. The catalysts were characterized by using various techniques (EDS, SEM, BET and XRD), confirming the effective deposition of Al/Zr pillared bentonite clay on the channel walls of cordierite monolith. The composite catalyst showed good mechanical stability after ultrasound treatment. The performance of the composite catalyst was evaluated in a catalytic plug flow reactor for continuous oxidation of phenol in terms of catalytic activity as well as their stability. The composite catalyst achieved high catalytic performance (100 % phenol conversion and 91 % total organic carbon reduction) with high stability after 140 h long experiment. During the CWAO of phenol reaction, aromatic ring intermediates (p-benzoquinone, catechol and hydroquinone) and short-chain carboxylic acids (oxalic acid, maleic acid, formic acid, acetic acid and malonic acid) were identified. Kinetic parameters of the model that describes the formation and oxidation of intermediate aromatic compounds and short-chain carboxylic acids were determined. The obtained experimental data results were described sufficiently with respect to phenol conversion. The proposed CWAO of the phenol kinetic model accounts for internal and external diffusion limitations, assuming the pseudo-first-order reaction. Therefore, synthesized monolithic catalysts have great potential for application in CWAO of phenol, since the materials used in the process are inexpensive, abundant and require minimal modifications.

Kinetics of aromatics hydrogenation on HBEA

Zeolite HBEA catalyzes hydrogenation of aromatic hydrocarbons—methyl-substituted benzenes (benzene and toluene), alkenyl-substituted benzenes (styrene), and polycyclics (naphthalene)—in presence of excess H2 at high-temperatures (573–748 K) with rates that depend linearly on aromatic and H2 pressures. The observed kinetic behavior can be rationalized based on a sequence of elementary steps where the first hydrogenation step of the adsorbed benzenic intermediate is rate-determining while subsequent hydrogenation and desorption steps are quasi-equilibrated and H+ is the most abundant surface species. Styrene hydrogenation exhibits the highest rates among the aromatics considered and results exclusively in ethylbenzene synthesis; in contrast, benzene/toluene and naphthalene hydrogenation results in formation of their triply-hydrogenated five-membered ring and doubly-hydrogenated ring open analogs, respectively. Based on independent studies involving co-reaction of cyclohexene and 1-methyl-1-cyclopentene with H2, we infer their facile interconversion and hydrogenation to methylcyclopentane implying that conversion of benzene to methylcyclopentane likely occurs via intervening formation of both five- and six-membered ring intermediates. Taken together, these studies demonstrate feasibility of aromatics hydrogenation and propensity of benzenic rings in these hydrocarbons to undergo ring reduction or ring opening during their activation with H2 on Brønsted acid zeolites.

Effect of residue substitution via site-directed mutagenesis on activity and steroselectivity of transaminase BpTA from Bacillus pumilus W3 for sitafloxacin hydrate intermediate

Aminotransferases are widely employed as biocatalysts for the asymmetric synthesis of biologically active pharmaceuticals. Transaminase BpTA from Bacillus pumilus W3 can accept a broad spectrum of sterically demanding substrates, but it does not process the key five-membered ring intermediate of sitafloxacin. In the present study, we rationally constructed numerous single-point mutants and six multi-point mutants by combining the structural characteristics of transaminase and its substrates. Biochemical characteristics of wild-type and mutant enzymes were initially analyzed, and mutants I215M, I215F, and Y32L displayed increased catalytic efficiency, K155A, I215V and T252A completely lost enzyme activity. Residues K155 and T252 had a particularly strong influence on catalytic activity. Four multi-point mutants (L212M/I215M, Y32L/S190A/L212M/I215M, Y32L/Y159F/T252A and Y32W/Y159F/I215M/T252A) possess potential for industrial production of the key five-membered ring intermediate of sitafloxacin. Furthermore, mutants Y32L/Y159F/T252A and Y32W/Y159F/I215M/T252A can catalyze conversion of (R)-α-phenethylamine, albeit at an extremely low rate (<8%). In summary, mutants L212M/I215M and Y32L/S190A/L212M/I215M are more suitable for industrial production of the antibiotic, sitafloxacin, via an enzymatic approach.