Diels-Alder Research Articles

Asymmetric Organocatalytic Diels-Alder Reaction of Olefinic Azlactones with Unsaturated Thiazolones: Access to Spirocyclohexenone Thiazolone Skeletons.

Chiral bifunctional thiourea-catalyzed Diels-Alder reaction between olefinic azlactones and alkylidene thiazolone derivatives is reported here for the first time. The asymmetric Diels-Alder reaction delivers vicinal tertiary-quaternary stereocenters in spirocyclohexenone thiazolones in moderate to high yields and good stereochemical outcomes. The protocol can be adapted to a broad array of substrates. Moreover, the reaction is scaled up, and the chiral spirocyclohexenone thiazolone was converted into valuable spirocyclic-1,2-amidoalcohol highlighting the synthetic utility of our methodology.

Total Synthesis of (+)-Brevianamides A and B.

(+)-Brevianamides A (1a) and B (1b) are distinguished by their unique bicyclo[2.2.2]diazaoctane structure and have captured the interest of synthetic chemists due to their fascinating array of biological activities. The biosynthetic proposal of these classes of alkaloids led to the discovery of a number of interesting strategies. We present a biomimetic synthesis of these alkaloids starting from naturally occurring 4-hydroxy-l-proline and L-tryptophan. Gratifyingly, we emulate an alternative biosynthetic process through a unique elimination-isomerization sequence triggered by a dual-base system to generate the key aza-diene required for the Diels-Alder reaction to craft the bicyclo[2.2.2]diazaoctane structure.

Preparation and thermal conductivity properties of CF/SR composites with high orientation and low interfacial thermal resistance based on the synergistic effect of magnetic field, torsional vibration and Diels-Alder reaction

Preparation and thermal conductivity properties of CF/SR composites with high orientation and low interfacial thermal resistance based on the synergistic effect of magnetic field, torsional vibration and Diels-Alder reaction

‘Clickable’ polymer brush coated magnetic nanoparticles: Employing Diels-Alder and azide-alkyne cycloaddition for modular targeted drug delivery platforms

Effective methods of multi-functionalization of nanomaterials are essential for fabricating effective targeted drug delivery systems. Herein, we disclose the fabrication of polymer brush-coated magnetic nanoparticles that could be functionalized with drugs and targeting ligands through orthogonal click reactions. In particular, polymers containing electron-rich furan groups as functionalization handles are grown from the surface of magnetic nanoparticles using the ‘graft-from’ approach. Furthermore, azide groups are installed at the chain end of polymer brushes to furnish an orthogonally functionalizable system. The attachment of maleimide-containing fluorescent dyes and cytotoxic drugs using the Diels-Alder reaction is demonstrated. Drug-conjugated nanoparticles functionalized with integrin-targeting peptide using the azide-alkyne cycloaddition reaction undergo preferential uptake in cancer cells and show dose-dependent cytotoxicity. We envision that the modularly functionalizable system disclosed here could target various cancer cells using an appropriate combination of drugs and targeting groups.

Catalytic co-pyrolysis of yellow poplar and HDPE using MOF-incorporated HY zeolite catalysts

Catalytic co-pyrolysis of yellow poplar and high-density polypropylene (HDPE) was conducted using metal oxide on hydrogen y-type (HY) zeolite to selectively produce monoaromatic hydrocarbons. The reaction was investigated using a tandem micro-reactor connected to a gas chromatography–mass spectrometry (GC–MS) system, encompassing both in-situ and ex-situ studies. Fe oxide/HY and Cu oxide/HY catalysts, prepared via a metal–organic framework (MOF)-incorporated technique, demonstrated excellent metal dispersion and enhanced electron density. The Cu oxide/HY catalyst showed significant production of benzene, toluene, ethylbenzene, and xylene, reaching up to 28% in in-situ studies. Owing to its strong acid sites, this catalyst facilitated the formation of aromatic compounds. In ex-situ studies, furan and acetaldehyde were consumed through the Diels–Alder reaction. The increase in aromatic compounds was highlighted by a synergistic effect percentage as high as 175%. The mechanism of aromatic formation was elucidated through dealkylation, Diels–Alder, and aromatization reactions. The Cu oxide/HY catalyst, combined with the MOF-incorporated preparation technique presents a promising system for catalytic co-pyrolysis of biomass and HDPE. This approach will facilitate efficient and sustainable aromatic hydrocarbon production from renewable and plastic waste sources.

Accurate carbon structure for prediction of reaction pathway during bio-coal production using torrefaction

The structural parameters of carbon were accurately determined through correction by employing a linear correlation method. Further, the nuclear Overhauser effect (NOE) was reduced in solid 13C-nuclear magnetic resonance spectra using a solid cross-polarization/magic angle spinning (CP/MAS) probe and the total suppression of sidebands sequence (TOSS). The reaction pathway during torrefaction was inferred from analysis of the accurate bond behavior and product distribution. The results show that torrefaction has a significant influence on the structural evolution of biomass. After correction, the relative deviations in the H/C ratio and aromaticity of the carbon structure decreased below 20 %. During torrefaction, the aliphatic carbon bonds were cleaved and aromatic carbon bonds were formed by dehydration, deoxygenation, oligomerization, aromatization, and Diels-Alder reaction. Torrefaction of biomass is divided into three stages. The first stage occurs below 220 °C, with disruption of the hydrogen bonds, a decrease in the number of Cal-O bonds, and the release of some CO2, CO, and furaldehyde. The second stage proceeds in the 220–260 °C range, where β-O-α bonds and glycoside bonds are broken, with the generation of ketones, furan, phenols, CO, and CO2. In the third stage between 260 and 300 °C, Cal-O and Cal-Cal bonds are broken. Bio-coal is composed of monomers of C20H14O3 with two aromatic rings linked by one aromatic ring. This significant, fundamental study enables accurate calculation and simulations for optimizing the industrial utilization of biomass.

Surprising Dynamics Phenomena in the Diels-Alder Reaction of C60 Uncovered with AI.

We performed an extensive artificial intelligence-accelerated quasi-classical molecular dynamics investigation of the time-resolved mechanism of the Diels-Alder reaction of fullerene C60 with 2,3-dimethyl-1,3-butadiene. In a substantial fraction (10%) of reactive trajectories, the larger C60 noncovalently attracts the 2,3-dimethyl-1,3-butadiene long before the barrier so that the diene undergoes the series of complex motions including roaming, somersaults, twisting, and twisting somersaults around the fullerene until it aligns itself to pass over the barrier. These complicated processes could be easily missed in typically performed quantum chemical simulations with shorter and fewer trajectories. After the barrier is passed, the bonds take longer to form compared to the simplest prototypical Diels-Alder reaction of ethene with 1,3-butadiene despite high similarities in transition states and barrier widths evaluated with intrinsic reaction coordinate (IRC) calculations. C60 is mainly responsible for these differences as its reaction with 1,3-butadiene is similar to the reaction with 2,3-dimethyl-1,3-butadiene: the only substantial difference being that the extra methyl groups double the probability of the prolonged alignment phase in dynamics. These additional calculations of C60 with 1,3-butadiene could be performed via active learning more easily by reusing the data generated for the other two reactions, showing the potential for larger-scale exploration of the effects of different substrates in the same types of reactions.

Insights into the thermal stabilization mechanism of zeolitic imidazolate framework-8 for poly(vinyl chloride)

The thermal stability of zeolitic imidazolate framework-8 (ZIF-8) for poly(vinyl chloride) (PVC) has received attention, but its thermal stabilization mechanism needs further clarification. Herein, the stearic acid-modified ZIF-8 with high specific surface area and large pore volume was effectively synthesized by using zinc stearate as the zinc source for the first time. Modification of stearic acid results in larger adsorption capacity of ZIF-8 for HCl and better thermal stability effect for PVC, especially long-term thermal stability. Moreover, the thermal stability mechanism of ZIF-8 for PVC was demonstrated by experiments and theoretical calculations. In addition to absorbing HCl to eliminate autocatalytic degradation of PVC, ZIF-8 disintegrates and may form 2-methylimidazole-Zn-Cl salt complex instead of free ZnCl2, avoiding the negative zinc burning effect. Furthermore, the Diels-Alder reaction between imidazole ring and degraded PVC prevents the extension of the conjugated double bonds of PVC and delays the deepening of the color of PVC.

Towards a Switchable Nanoparticle Behavior Using Inverse Electron-Demand Diels-Alder Chemistry and Ectoenzyme-Based Ligand Activation

Nanoparticles (NPs) as drug delivery platforms encounter numerous obstacles on their journey from administration to the target site. Often, diametrically opposing particle properties are desirable to overcome biological and physical barriers. Therefore, stimuli-responsive NPs have been developed to allow for specific particle adaptation. In this work, it was demonstrated that NPs can be rendered switchable with respect to their interaction with a receptor through an external chemical stimulus. A combination of the inverse electron-demand Diels-Alder (iEDDA) reaction for subsequent NP functionalization and ectoenzyme-based ligand activation allowed for specific particle tailoring. Building on this, a two-step process for target cell recognition was developed: First, NPs were functionalized with Angiotensin-I (Ang-I) as inactive ligand using iEDDA chemistry. At the target site, the ligand was enzymatically processed to Angiotensin-ll (Ang-II) by cellular ectoenzymes. Ang-ll binds as active ligand to the angiotensin ll type 1 (AT1) receptor on the target cell surface. This enzymatic activation aims to minimize the biological effect of the ligand prior to particle binding, while the NP target cell specificity is increased by a two-step recognition with enzymatic processing and receptor binding.

Catalytic asymmetric inverse-electron-demand Diels–Alder reaction of 2-pyrones with aryl enol ethers

Chiral aryl cyclohex-3-en ether scaffold is widely present in bioactive natural products and drugs. The exploitation of efficient and enantioselective methods for the construction of aryl cyclohex-3-en ether scaffold is significant. Herein we disclose a chiral N,N’-dioxide/Lewis acid complex-catalyzed asymmetric inverse-electron-demand Diels–Alder (IEDDA) reaction using electron-deficient 3-carboalkoxyl-2-pyrones and less electron-enriched aryl enol ethers as reactants. A wide range of non- and 1,2-disubstituted acyclic aryl enol ethers are applicable to deliver diverse chiral bridged bicyclic lactones in high yields and stereoselectivities (up to 95% yield, >20:1 dr, 97:3 er). The bridged bicyclic lactone core can be easily converted into chiral aryl cyclohex-3-en ether scaffold. Notably, DFT calculations revealed a stepwise and endo mechanism to explain the high enantioselectivity controlled by the cooperative effect of the steric factors and the dispersion interactions between ligands and enol ethers.

Preparation of Large Perphenylbiaryls: Can Intermolecular Coupling Compete with Intramolecular Cyclization of Precursors?

The highly substituted naphthalenes 1,2,3,4,5,6,7-heptaphenylnaphthalene (13), 2,3,4,5,6,7,8-heptaphenyl-1-naphthol (12), 1-bromo-2,3,4,5,6,7,8-heptaphenylnaphthalene (4), and 1-(phenylethynyl)-2,3,4,5,6,7,8-heptaphenylnaphthalene (5) were prepared by a variety of methods, and all but 5 were crystallographically characterized. The attempted Ullmann coupling of 4 to give tetradecaphenyl-1,1'-binaphthyl (3), at both 270 °C and 350 °C, yielded instead 1,2,3,4,5,6-hexaphenylfluoranthene (17) via an intramolecular cyclization reaction. When the alkyne 5 was heated with tetracyclone (6) at 350 °C, 1-(pentaphenylphenyl)-2,3,4,5,6,7,8-heptaphenylnaphthalene (7) was formed in 3% yield. However, greater amounts of 5,6,7,8,9,14-hexaphenyldibenzo[a,e]pyrene (20, 11%) and 1,2,3,4,5,6,7-heptaphenylfluoranthene (21, 11%) were produced, the former by intramolecular cyclization and dehydrogenation of 5 and the latter by an intramolecular Diels-Alder reaction of 5 followed by extrusion of acetylene. The X-ray structure of 7 shows it to be an exceptionally crowded biaryl, and the X-ray structure of 20 shows it to be a saddle shaped polycyclic aromatic hydrocarbon.

Wave-transparent and eco-friendly flame-retardant phosphorus-based phthalonitrile/quartz composites by a synchronized self-curing strategy with cyano and alkynyl groups

The robust human–machine interaction systems of the aerospace industry necessitate the development of thermal resistant wave-transparent composites, with a pivotal focus on organic resin matrix. However, enhancing the heat resistance of such materials while preserving other critical attributes has been a formidable challenge. In this study, a novel designed strategy of a dual-curing functional phosphorus-based phthalonitrile monomer (P-ALK-PN) has been proposed. The optimized curing temperatures for intra- or intermolecular Diels-Alder reactions of alkynyl groups and polyaddition reaction of cyano groups resulted in a homogeneous and highly crosslinked N-enriched phthalonitrile system. After curing at 450 °C, the resin, namely P-ALK-PN-450 °C, demonstrated exceptional thermal stability (T5% = 644 °C), thermo-oxidative stability (T5% = 554 °C), and char yield at 800 °C (90.7 % in N2 and 67.5 % in air). Their quartz fiber reinforced composites (P-ALK-PN/QFs) were subsequently fabricated by the hot-pressing process. Upon post-curing at 420 °C, P-ALK-PN-420 °C/QF displayed elevated glass transition temperature (550 °C), flexural strength (319 MPa), and relatively low dielectric properties with a dielectric constant (Dk) of approximately 4.2 and a dissipation factor (Df) less than 0.02 across a wide temperature ranging from 25 °C to 600 °C. Especially, it exhibited excellent flame retardancy (only a 6.7 % weight loss at ambient temperatures exceeding 1300 °C for 200 s) as well, stemming from release of eco-friendly inert gases (NH3) and formation of a graphitized protective layer during pyrolysis. These promising results highlight the potential applications of P-ALK-PN resins in aerospace and high-performance engineering fields.

Synthesis and Characterization of New Compounds by Enzymatically Catalysed Diels-Alder Reactions

The Diels-Alder (DA) reaction is one of the important chemical transformations to create the C–C bonds with predicted regio- and stereo-selectivity, which lead to the forming of bulk organic molecules. Despite of the significant efforts in this filed, the control of the stereoselectivity of DA reactions remain so difficult. Despite the significant efforts in this field, controlling of stereoselectivity of DA reactions remains so difficult. The design of the enzymatic DA reactions provides scientists with a huge advantage in increasing the selectivity of DA reaction products. This work aims to apply the friendly environmental method includes the application of the current approach in enzymatic DA reactions by formation the new organic compounds through the enzymatic DA reactions between anthracene derivatives as dines and pyrrole derivatives as dienophiles. All DA reactions were curried out in the inert environment using the nitrogen gas. The prepared compounds were caramelized using various techniques including mass spectroscopy, nuclear magnetic resonance, and Fourier transform infrared. The results showed that all products of DA reactions containing unnatural dienes with endo-configuration, in addition to obtain 53%–94% isolated yields. Consequently, this study provides an efficient method to control the stereochemistry of DA reactions.

A "Bottom-Up" Strategy for High-Performance Benzocyclobutene (BCB)-Subnanometer Inorganic Nanocomposites.

Developing benzocyclobutene (BCB) nanocomposites with ultra-small inorganic sizes represents a formidable challenge, although it offers great potential to produce materials with customizable structural and rich functional properties. In this study, we present a "bottom-up" design strategy for creating cross-linked benzocyclobutene (BCB) nanocomposites with highly dispersed nanodomains, such as organoalkoxysilane. This approach leverages ring-opening metathesis polymerization (ROMP) and thermally induced cycloaddition reactions to embed oligomeric silsesquioxanes, achieving a unique molecular structure with promising low-dielectric applications. The synthesis involves organoalkoxysilane and BCB as pendant groups of polynorbornenes that are covalently integrated. Additionally, the methoxyl groups of linear polymers could be further hydrolyzed under acidic conditions, and BCB groups could undergo thermal-induced ring-opening at high temperatures and Diels-Alder addition between themselves and vinyl groups, respectively. Fourier transform infrared (FTIR) spectroscopy analyses suggested the presence of ladder or network structures and high-resolution transmission electron microscopy (HRTEM) images presented the well-dispersed inorganic clusters, facilitating excellent dielectric properties with a dielectric constant (Dk) of 2.25 and a dissipation factor (Df) of 2.27 × 10-4. Compared with previously reported low-Dk materials, the cured nanocomposites also exhibited a significantly balanced enhancement of their comprehensive properties. This molecular bottom-up strategy provided a simple and universal method for constructing BCB-inorganic nanocomposites featuring a subnanometer inorganic structure, paving the way for future investigation into new classes of polymer-inorganic nanocomposites with a low Dk.

Construction of acenaphthylenes via C-H activation-based tandem penta- and hexaannulation reactions.

Acenaphthylene-containing polycyclic aromatic hydrocarbons (AN-PAHs) are noteworthy structural motifs for organic functional materials due to their non-alternant electronic structure, which increases electron affinity. However, the synthesis of AN-PAHs has traditionally required multiple sequential synthetic steps, limiting structural diversity. Herein, we present a tandem C-H penta- and hexaannulation reaction of aryl alkyl ketone with acetylenedicarboxylate. This integrated approach enhances overall efficiency and selectivity, marking a significant advancement in AN-PAH synthesis. Mechanistic studies unveil an orchestrated extension of five- and six-membered rings through C-H activation-annulation and Diels-Alder reaction. Additionally, the tandem annulation reaction can be performed stepwise, further validating the proposed mechanism and increasing the structural diversity of AN-PAHs.

Highly dispersed palladium supported on sulfuric acid-modified activated carbon for efficient dehydrogenation to produce novel aromatic monomer

Herein, a sustainable route to novel aromatic monomer, dimethyl 1,2,3,4-tetrahydro-1,4-methanonaphthalene-5,8-dicarboxylate, was developed, in which dimethyl muconate and norbornene used as the diene and dienophile undergo Diels-Alder reaction followed by dehydrogenation. The polycyclic cycloadduct, octahydro-1,4-methanonaphthalene-5,8-dicarboxylate, could be synthesized without catalyst. The activated carbon modified with sulfuric acid generated more oxygen-containing groups, stronger acidity and more acidic sites. Highly dispersed palladium metal particles with an average particle size of about 1.0 nm exhibited excellent activity in the dehydrogenation reaction and the yield of target product reached 73.8 %.

Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide

AbstractHere we report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu‐promoted dienyl enolization, intramolecular Diels–Alder reaction and enol‐ketone tautomerization to afford pedrolide, a pathway consistent with our proposal for the biogenesis of pedrolide.

Molecular Editing of Pyrroles to Benzenes/Naphthalenes by N2O Deletion.

A molecular editing reaction for converting pyrrole rings into benzene rings through a sequential pathway of Diels-Alder and cheletropic reactions was developed. The nitrogen atom in a N-bridged intermediate is eliminated in the form of N2O by a strain-releasing pathway, ultimately leading to the formation of substituted benzene and naphthalene derivatives.

Analysis and Formation of Polycyclic Aromatic Hydrocarbons in Canned Minced Chicken and Pork during Processing.

Polycyclic aromatic hydrocarbons (PAHs) represent important toxic compounds formed in meat products during processing. This study aims to analyze 22 PAHs by QuEChERS coupled with GC-MS/MS in canned minced chicken and pork during processing. After marinating raw minced chicken and pork separately with a standard flavoring formula used for canning meat in Taiwan, they were subjected to different processing conditions including stir-frying, degassing and sterilizing at 115 °C/60 min (low-temperature-long-time, LTLT) and 125 °C/25 min (high-temperature-short-time, HTST). The quantitation of PAHs in these meat products revealed the formation of only three PAHs including acenaphthylene (AcPy), acenaphthene (AcP) and pyrene (Pyr) in canned minced chicken and pork during processing with no significant difference in total PAHs between the meat types. Analysis of PAH precursors showed the presence of benzaldehyde at the highest level, followed by 2-cyclohexene-1-one and trans,trans-2,4-decadienal in canned minced chicken and pork, suggesting PAH formation through the reaction of benzaldehyde with linoleic acid degradation products and of 2-cyclohexene-1-one with C4 compounds through the Diels-Alder reaction, as well as the reaction of trans,trans-2,4-decadienal with 2-butene. Monounsaturated and polyunsaturated fatty acids were present in the largest proportion in LTLT-sterilized chicken/pork, followed by HTST-sterilized chicken/pork and raw chicken/pork, and their levels did not show a high impact on PAH formation, probably due to an insufficient heating temperature and length of time. A two-factorial analysis suggested that PAH formation was not significantly affected by the sterilization condition or meat type. Principal component analysis corroborated the observed results implying the formation of PAHs in canned minced chicken/pork under different processing conditions with an insignificant difference (p > 0.05) between them, with the individual PAH content following the order of Pyr > AcPy > AcP.

Physics-Informed Active Learning for Accelerating Quantum Chemical Simulations.

Quantum chemical simulations can be greatly accelerated by constructing machine learning potentials, which is often done using active learning (AL). The usefulness of the constructed potentials is often limited by the high effort required and their insufficient robustness in the simulations. Here, we introduce the end-to-end AL for constructing robust data-efficient potentials with affordable investment of time and resources and minimum human interference. Our AL protocol is based on the physics-informed sampling of training points, automatic selection of initial data, uncertainty quantification, and convergence monitoring. The versatility of this protocol is shown in our implementation of quasi-classical molecular dynamics for simulating vibrational spectra, conformer search of a key biochemical molecule, and time-resolved mechanism of the Diels-Alder reaction. These investigations took us days instead of weeks of pure quantum chemical calculations on a high-performance computing cluster.