Diels-Alder Research Articles

Regioselective Diels–Alder Reactions of C70 Directed by Endohedral Ca and Th Atoms

Regioselective Diels–Alder Reactions of C₇₀ Directed by Endohedral Ca and Th Atoms

Front Cover: Solid‐State Generation of Diarylisonaphthofuran and Its Mechanochemical Diels–Alder Reaction with Epoxynaphthalene (Chem. Eur. J. 69/2023)

Front Cover: Solid‐State Generation of Diarylisonaphthofuran and Its Mechanochemical Diels–Alder Reaction with Epoxynaphthalene (Chem. Eur. J. 69/2023)

Solid-State Generation of Diarylisonaphthofuran and Its Mechanochemical Diels-Alder Reaction with Epoxynaphthalene.

Invited for the cover of this issue are Toshiyuki Hamura and co-workers at Kwansei Gakuin University. The image depicts solid-state generation of diarylisonaphthofuran from 1,3-diaryl-1,3-dihydronaphthofuranol and its mechanochemical Diels-Alder reaction with epoxynaphthalene. Read the full text of the article at 10.1002/chem.202302660.

Fabrication of well-defined lignin-derived elastomers by atom transfer radical polymerization and Diels-Alder reaction towards sustainable, super-tough and high temperature-resistant hot-melt adhesives

Hot-melt adhesives synthesized from sustainable resource have attracted increasing attention in fields of home decoration, handicraft production, automotive industries, etc., due to their free of volatile organic compounds (VOCs) and environmentally friendly advantages. However, it is still challenging to fabricate super-tough and heat-resistant hot-melt adhesives with utilization of the inherited properties of sustainable resource as feedstock. Herein, a combination of photoinduced metal-free atom transfer radical polymerization (ATRP) and Diels-Alder (DA) reaction was applied to prepare lignin-derived elastomers for super-tough and high temperature-resistant hot-melt adhesives. Firstly, photoinduced metal-free ATRP of lauryl methacrylate (LMA) derived from fatty acids and furfuryl methacrylate (FMA) derived from furfural, were employed to fabricate sustainable well-defined multi-arm lignin-graft copolymers bearing furfuryl groups with the aid of lignin based macro-initiator (L-Br). The photoinduced metal-free ATRP in this work could be activated and deactivated by an “ON–OFF” ultraviolet (UV) light switch, and successfully achieved the precise control over the molecular weight and composition of lignin-graft copolymers. Then, Diels-Alder (DA) reaction was applied to functionalize the lignin-graft copolymers with dynamic crosslinked network and obtain the lignin-derived elastomers. Benefiting from the multi-arm structure and the dynamic crosslinked network, these lignin-derived elastomers exhibited favorable mechanical property, thermal stability, shape memory, self-healing and recycled properties. In addition, the lignin-derived elastomers could be used as hot-melt adhesives and their lap shear strengths could reach 5.95 MPa, while being bonded with aluminum plates. Moreover, the steel plate bonded with lignin-derived elastomers could remain stable even at 100 °C. We believe that this work will offer a new approach for designing lignin-derived elastomers towards sustainable, strong, super-tough and high-temperature-resistant hot-melt adhesives.

A DFT study on substituents, solvent, and temperature effect and mechanism of Diels-Alder reaction of hexafluoro-2-butyne with furan.

Furan and its derivatives constitute a vital class of heterocyclic chemistry used widely in organic synthesis via Diels-Alder reactions. As fluorine incorporation has been of great interest due to the limited possible pathways, the present study on [4 + 2] cycloaddition Diels-Alder reaction, between hexafluoro-2-butyne and 2-substituted (NH2, OCH3, OTMS, NHBoc) furans, uses the reaction as a likely route. The computational study revealed that that the reaction is feasible in all conditions and is most favorable for NH2 substituent in furan. The study of the effect of temperature has depicted that low temperature favors the formation of adducts, while the rise in temperature prefers ring opening to form 4-substituted-2,3-di(trifluoromethyl)phenol derivatives. The feasibility of a reaction has been determined by Gibbs energy change. The transition state study has been performed to find the activation energy, C-C single bond formation and global electron density transfer (GEDT) involved in the adduct formation. MEP plots have been used to understand the region of electrophilicity and nucleophilicity character. Furthermore, the mechanism for the formation of phenol products has been discussed. The decomposition of the NHBoc group at higher temperatures has been proved via a proposed mechanism and compared with experimental results. The reaction was theoretically investigated using B3LYP hybrid functional with 6-311 + G(d,p) basis sets, in gas phase and under different solvent conditions like water, acetonitrile, and THF. The transition state structures of the adduct were optimized at the lower basis set B3LYP/6-31 + G(d,p) as well as at the higher basis set B3LYP/6-311 + G(d,p) level. The changes in Gibbs energy (∆G) for the formation of products at different temperatures and in various solvents have been calculated at B3LYP/6-311 + G(d,p) level.

Reductive Release from a Hybrid PKS-NRPS during the Biosynthesis of Pyrichalasin H.

Three central steps during the biosynthesis of cytochalasan precursors, including reductive release, Knoevenagel cyclisation and Diels Alder cyclisation are not yet understood at a detailed molecular level. In this work we investigated the reductive release step catalysed by a hybrid polyketide synthase non-ribosomal peptide synthetase (PKS-NRPS) from the pyrichalasin H pathway. Synthetic thiolesters were used as substrate mimics for in vitro studies with the isolated reduction (R) and holo-thiolation (T) domains of the PKS-NRPS hybrid PyiS. These assays demonstrate that the PyiS R-domain mainly catalyses an NADPH-dependent reductive release of an aldehyde intermediate that quickly undergoes spontaneous Knoevenagel cyclisation. The R-domain can only process substrates that are covalently bound to the phosphopantetheine thiol of the upstream T-domain, but it shows little selectivity for the polyketide.

Synthesis of novel biphenyl‐fused alicyclic tetracarboxylic dianhydride and its performance in thermostable and transparent colorless polyimides

AbstractBiphenyl fused alicyclic tetracarboxylic dianhydride, 6,6′,7,7′‐tetracarboxylic dianhydride‐5,5′,6,6′,7,7′,8,8′‐octahydro‐2,2′‐binaphthalene (OHBNDA) was successfully synthesized from biphenyltetracarboxylic dianhydride (BPDA) through hydrolysis, reduction, bromination, and Diels–Alder reaction. Three OHBNDA‐based polyimides (PIs) were synthesized by one‐step polycondensation at high temperature with 9,9‐bis(4‐aminophenyl)fluorene (BAFL), 2,2′‐bis(trifluoromethyl)‐4,4′‐diaminobiphenyl (TFMB), and 4,4′‐diamino‐2,2′‐dimethyl‐1,1′‐biphenyl (m‐TolDA) diamines, respectively. These PIs have moderate molecular weights and good solubility in polar organic solvents, such as N,N‐dimethylformamide, dimethylacetamide (DMAc), and dimethyl sulfoxide (DMSO). OHBNDA‐TFMB, OHBNDA‐m‐TolDA, and OHBNDA‐BAFL display glass transition temperatures (Tgs) of 309, 329, and 377°C from differential scanning calorimetry (DSC) curves, and the decomposition temperatures at 5% weight loss (Td5) of as high as 522, 507, and 548°C under nitrogen, respectively. Meanwhile, these PI films also show good optical transparency with the cut‐off wavelength <315 nm and the transmittance >75% at 400 nm. These results confirm that aryl‐fused alicyclic tetracarboxylic dianhydrides can afford transparent/colorless PIs with high thermal stability, especially the higher decomposition temperatures than the wholly alicyclic dianhydrides.

Steam reforming of n-butanol and tetrahydrofuran: Influence of aliphatic carbon chain and furan ring on coking behaviors

Almost all small organics, in theory, could be potential feedstock for production of hydrogen via steam reforming (SR). Nevertheless, not all organics contain a linear carbon chain like ethanol or acetone. How do ring structure of an organic substrate impacted coking behaviors in SR were explored herein with n-butanol and tetrahydrofuran (THF) as the research objects over Ni/SiO2 catalyst, due to the same carbon number but distinct carbon chains in these two molecules. The results indicated that furan ring in THF lowered reactivity towards SR, as its adsorption on metallic sites was more difficult than n-butanol. The in-situ IR analysis for measuring reaction intermediates suggested that n-butanol and THF involved generation of intermediates with CO formed via dehydrogenation, CxHy formed via cracking and CC species that can be further gasified or aggregate to coke. However, more oxygenated intermediates generated in SR of n-butanol than in THF, rendering n-butanol more reactive towards SR. This, however, also formed substantially more coke of aliphatic nature in amorphous form, which led to the coke of thermally unstable and had higher tendency being oxidized. In converse, coke formed from SR of THF was more aromatic, showing less impact on catalytic activity, higher thermal stability, and larger crystal size with more carbon nanotube form of coke. This was closely connected with the ring structures that could dehydrogenated to form the unsaturated ring with capability to involve in Diels-Alder reactions, forming coke of aromatic nature.

(±)-Salvicatone A: A Pair of C27-Meroterpenoid Enantiomers with Skeletons from the Roots and Rhizomes of Salvia castanea Diels f. tomentosa Stib.

(±)-Salvicatone A (1), a C27-meroterpenoid featuring a unique 6/6/6/6/6-pentacyclic carbon skeleton with a 7,8,8a,9,10,10a-hexahydropyren-1 (6H)-one motif, was isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Its structure was characterized by comprehensive spectroscopic analyses along with computer-assisted structure elucidation, including ACD/structure elucidator and quantum chemical calculations with 1H/13C NMR and electronic circular dichroism. Biogenetically, compound 1 was constructed from decarboxylation following [4 + 2] Diels-Alder cycloaddition reaction between caffeic acid and miltirone analogue. Bioassays showed that (-)-1 and (+)-1 inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophage cells with an IC50 value of 6.48 ± 1.25 and 15.76 ± 5.55 μM, respectively. The structure-based virtual screening based on the pharmacophores in ePharmaLib, as well as the molecular docking and molecular dynamics simulations study, implied that (-)-1 and (+)-1 may potentially bind to retinoic acid receptor-related orphan receptor C to exert anti-inflammatory activities.

Tung oil-based waterborne UV-curable coatings via cellulose nanofibril stabilized Pickering emulsions for self-healing and anticorrosion application

In this study, waterborne UV-curable coatings with self-healing properties based on transesterification were prepared using renewable biomass resources for anti-corrosion application. Tung oil (TO)-based oligomer (TMHT) was synthesized through Diels-Alder reaction of TO with maleic anhydride, subsequent ring opening reaction with hydroxyethyl acrylate (HEA), and final neutralize reaction with triethylamine. A series of waterborne UV-curable coatings were prepared from cellulose nanofibrils (CNF) stabilized TMHT-based Pickering emulsions after drying and UV light-curing processes. It is suggested that CNF significantly improved the storage stability of Pickering emulsions. The obtained waterborne UV-curable coatings with CNF of 1–3 wt% exhibited remarking coating and mechanical performance (pencil hardness up to 5 H, adhesion up to 2 grade, flexibility of 2 mm, tensile strength up to 11.6 MPa, etc.), great transmittance (82.3 %–80.8 %) and great corrosion resistance (|Z|0.01Hz up to 5.4 × 106 Ω·cm2). Because of the presence of the dynamic ester bonds in TMHT, the coatings exhibited excellent self-healing performance (78.05 %–56.34 %) at 150 °C without catalyst and external force. More importantly, the |Z|0.01Hz of the self-healing coating was higher than that of the scratched coating, indicating that the self-healing performance could extend the service life of the coating in corrosion resistant application.

Easy Access to Phenanthridinones via Metal-Free Cascade Benzannulation and C-N Bond Formation.

A concise route for the synthesis of dihydrobenzo[j]phenanthridinones has been disclosed through an aryne annulation strategy under metal-free reaction conditions. The reaction involves multiple C-C and C-N bond cleavages/formations via Diels-Alder reaction, aromatization-driven C-N bond cleavage, and amide formation.

Esterase-Responsive Polyglycerol-Based Nanogels for Intracellular Drug Delivery in Rare Gastrointestinal Stromal Tumors.

Rare gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and PDGFRA genes. Avapritinib (BLU-285) is a targeted selective inhibitor for mutated KIT and PDGFRA receptors that can be used to treat these tumors. However, there are subtypes of GISTs that exhibit resistance against BLU-285 and thus require other treatment strategies. This can be addressed by employing a drug delivery system that transports a combination of drugs with distinct cell targets. In this work, we present the synthesis of esterase-responsive polyglycerol-based nanogels (NGs) to overcome drug resistance in rare GISTs. Using inverse nanoprecipitation mediated with inverse electron-demand Diels-Alder cyclizations (iEDDA) between dPG-methyl tetrazine and dPG-norbornene, multi-drug-loaded NGs were formed based on a surfactant-free encapsulation protocol. The obtained NGs displayed great stability in the presence of fetal bovine serum (FBS) and did not trigger hemolysis in red blood cells over a period of 24 h. Exposing the NGs to Candida Antarctica Lipase B (CALB) led to the degradation of the NG network, indicating the capability of targeted drug release. The bioactivity of the loaded NGs was tested in vitro on various cell lines of the GIST-T1 family, which exhibit different drug resistances. Cell internalization with comparable uptake kinetics of the NGs could be confirmed by confocal laser scanning microscopy (CLSM) and flow cytometry for all cell lines. Cell viability and live cell imaging studies revealed that the loaded NGs are capable of intracellular drug release by showing similar IC50 values to those of the free drugs. Furthermore, multi-drug-loaded NGs were capable of overcoming BLU-285 resistance in T1-α-D842V + G680R cells, demonstrating the utility of this carrier system.

Neighboring Molecular Engineering in Diels-Alder Chemistry Enabling Easily Recyclable Carbon Fiber Reinforced Composites.

Although a variety of dynamic covalent bonds have been successfully used in the development of diverse sustainable thermosetting polymers and their composites, solving the trade-off between recovery efficiency and comprehensive properties is still a major challenge. Herein, a "one-stone-two-birds" strategy of lower rotational energy barrier (Er) phosphate-derived Diels-Alder (DA) cycloadditions was proposed for easily recyclable carbon fiber (CF)-reinforced epoxy resins (EPs) composites. In such a strategy, the phosphate spacer with lower Er accelerated the segmental mobility and dynamic DA exchange reaction for network rearrangement to achieve high-efficiency repairing, reprocessing of the EPs matrix and its composites and rapid nondestructive recycling of CF; meanwhile, incorporating phosphorus-based units especially reduced their fire hazards. The resulting materials simultaneously showed excellent thermal/mechanical properties, superb fire safety and facile recyclability, realizing the concept of recycling for high-performance thermosetting polymers and composites. This strategy is of great significance for understanding and enriching the molecular connotation of DA chemistry, making it potentially applicable to the design and development of a wide range of dynamic covalent adaptable materials toward practical cutting-edge-tech applications.

Neighboring Molecular Engineering in Diels–Alder Chemistry Enabling Easily Recyclable Carbon Fiber Reinforced Composites

AbstractAlthough a variety of dynamic covalent bonds have been successfully used in the development of diverse sustainable thermosetting polymers and their composites, solving the trade‐off between recovery efficiency and comprehensive properties is still a major challenge. Herein, a “one‐stone‐two‐birds” strategy of lower rotational energy barrier (Er) phosphate‐derived Diels–Alder (DA) cycloadditions was proposed for easily recyclable carbon fiber (CF)‐reinforced epoxy resins (EPs) composites. In such a strategy, the phosphate spacer with lower Er accelerated the segmental mobility and dynamic DA exchange reaction for network rearrangement to achieve high‐efficiency repairing, reprocessing of the EPs matrix and its composites and rapid nondestructive recycling of CF; meanwhile, incorporating phosphorus‐based units especially reduced their fire hazards. The resulting materials simultaneously showed excellent thermal/mechanical properties, superb fire safety and facile recyclability, realizing the concept of recycling for high‐performance thermosetting polymers and composites. This strategy is of great significance for understanding and enriching the molecular connotation of DA chemistry, making it potentially applicable to the design and development of a wide range of dynamic covalent adaptable materials toward practical cutting‐edge‐tech applications.

A mild catalyzed imino Diels-Alder reaction for the synthesis of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide derivatives as regulators of Quorum Sensing in Pseudomonas aeruginosa

Bacterial resistance is one of the major global public health problems. In addition, virulence factors promoted multiple drug resistance through cell-to-cell communications by molecules within microbial communities, denominated Quorum Sensing (QS). The regulation of QS by small molecules appears as a therapeutic alternative through the use of synthetic analogs of agonists. The present work developed the construction of a series of derivatives of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl) formamide (1a-h) via Povarov-type sequential reactions to deliver the tetrahydroquinoline (THQ) derivatives in moderate to good yields (24–78%). To evaluate the potential in molecular diversity of THQ-type autoinducers, a study of these agents as potential inhibitors of bacterial growth and virulence factors involved in QS systems on P. aeruginosa was carried out both as antibacterial evaluation on E. coli strain. THQs showed significant activity values for molecules with halogen substituents at the C-6 position (-F, -Cl, and I), revealing at a concentration of 75 µg/mL a percentage inhibition between 27 and 40%. Furthermore, autoinducers with halogen substitutes in phenotypic studies on P. aeruginosa showed good results. Also, they exhibited weak formation of both biofilm and low pyocyanin formation, which are indicators of virulence in P. aeruginosa. Overall, the results suggest that compound N-(6-fluor-2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide (1a) stands out as the most representative within this series of THQ derivatives.

Synthesis of polyurethane hot melt adhesive without solvent via Diels-Alder reaction

Polyurethane hot melt adhesive was synthesized without any solvent via Diels-Alder (DA) reaction between furan terminated prepolymer and bismaleimide (BMI) and was coded as PU-DA-NS. Firstly the DA reaction was inhibited at higher temperature (110 °C) to reduce the viscosity and benefit the contact of furan terminated prepolymer and BMI. Consequently, PU-DA-NS was obtained via DA reaction at lower temperature (70 °C). The structure of PU-DA-NS was investigated via 1H NMR, DSC and TGA. The results showed that the solvent-free preparation cannot reach the reaction degree of solvent preparation, due to the contact of the reactants cannot be as good as preparation in solvent such as DMF, although the higher temperature decreased the viscosity of the reactant. However the heating and pressing procedure during the adhesive process destroyed the looser structure and increased the adhesive tensile strength to 70 % of PU-DA synthesized via solvent preparation.

Mechanistic Studies of Regiocontrolled Bisaddition of Fullerenes Driven by Oriented External Electric Fields.

The challenge of achieving regioselective multifunctionalization on highly symmetric C60 and C70 fullerenes persists as a significant hurdle. In this study, we present a novel approach involving the participation of an oriented external electric field (OEEF) to facilitate the regioselective formation of bisadducts in C60/C70 fullerenes. These products are obtained through consecutive Diels-Alder cycloaddition reactions. We constructed the field strength-barrier relationship and elucidated the OEEF-driven modulation mechanisms quantitatively. Leveraging the interplay between molecular dipoles and electric fields, the diverse reactions at distinct sites exhibit varying degrees of sensitivity to the applied electric fields, thereby leading to a pronounced regioselectivity in the bisaddition process. Our proposition suggests that the angle formed between the bonding direction (referred to as the reaction axis) and the external field can conveniently function as a predictive descriptor for the reactivity of different sites on the fullerene surface when subjected to electric fields.

Solvent effects on Diels–Alder reaction in ionic liquids: A reaction density functional study

Extensive experimental studies have been performed on the Diels–Alder (DA) reactions in ionic liquids (ILs), which demonstrate that the IL environment can significantly influence the reaction rates and selectivity. However, the underlying microscopic mechanism remains ambiguous. In this work, the multiscale reaction density functional theory is applied to explore the effect of 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) solvent on the reaction of cyclopentadiene (CP) with acrolein, methyl acrylate, or acrylonitrile. By analyzing the free energy landscape during the reaction, it is found that the polarization effect has a relatively small influence, while the solvation effect makes both the activation free energy and reaction free energy decrease. In addition, the rearrangement of local solvent structure shows that the cation spatial distribution responds more evidently to the reaction than the anion, and this indicates that the cation plays a dominant role in the solvation effect and so as to affect the reaction rates and selectivity of the DA reactions.

Synthesis and Preclinical Fluorescence Imaging of Dually Functionalized Antibody Conjugates Targeting Endothelin Receptor-Positive Tumors.

For the past two decades, the emerging role of the endothelin (ET) axis in cancer has been extensively investigated, and its involvement in several mechanisms described as "hallmarks of cancer" has clearly highlighted its potential as a therapeutic target. Despite the growing interest in finding effective anticancer drugs, no breakthrough treatment has successfully made its way to the market. Recently, our team reported the development of a new immuno-positron emission tomography probe targeting the ET A receptor (ETA, one of the ET receptors) that allows the successful detection of ETA+ glioblastoma, paving the way for the elaboration of novel antibody-based strategies. In this study, we describe the synthesis of two PET/NIRF (positron emission tomography/near-infrared fluorescence) dually functionalized imaging agents, directed against ETA or ETB, that could be used to detect ET+ tumors and select patients that will be eligible for fluorescence-guided surgery. Both imaging modalities were brought together using a highly versatile tetrazine platform bearing the IRDye800CW fluorophore and desferrioxamine for 89Zr chelation. This so-called monomolecular multimodal imaging probe was then "clicked", via an inverse-electron-demand Diels-Alder reaction, to antibodies conjugated site-specifically with a trans-cyclooctene group. This approach has led to homogeneous and well-defined constructs that retained their high affinity and high specificity for their respective target, as shown by flow cytometry and NIRF in vivo imaging experiments in nude mice bearing CHO-ETA and CHO-ETB tumors. Ultimately, these bimodal immunoconjugates could be used to improve the outcomes of patients with ET+ tumors.

Examination of Diels–Alder/Tsuji–Trost Route towards Kopsia Alkaloids

AbstractA reaction sequence of Diels–Alder cycloaddition and Tsuji–Trost allylation was examined in terms of its application to the synthesis of kopsinine and the related Kopsia alkaloids. Results of the studies in two synthetic directions are presented herein: 1) synthesis of the properly substituted diene, required for the Diels–Alder step; and 2) model studies and optimization of the key reaction sequence in the absence of side-chain. Details on the challenging introduction of the side-chain into tetrahydrocarboline ketone and its silylation, resulting in rare but unproductive vinylogous Claisen cyclization, and the successful Mannich/Mukaiyama aldol sequence are disclosed in the first direction. In the second direction, the endo-selective Diels–Alder reaction with allyl acrylate and Tsuji–Trost allylation providing incorrect stereochemistry are disclosed. Interaction of both dienes with an alkyne provides carbazoles via Alder–Rickert reaction.