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Diels-Alder cycloadditions involving furans and maleimides are extensively used in organic chemistry and materials synthesis. Given the promising advances of organoruthenium complexes in therapy, we explored the possibility of exploiting such Diels-Alder linkages as a mean to modulate their biological properties.

Both shape memory and self-healing polymers have received significant attention from the materials science community. The former, for their application as actuators, self-deployable structures, and medical devices; and the latter, for extending the lifetime of polymeric products. Both effects can be stimulated by heat, which makes resistive heating a practical approach to trigger these effects. Here we show a conductive polyketone polymer and carbon nanotube composite with cross-links based on the thermo-reversible furan/maleimide Diels–Alder chemistry. This approach resulted in products with efficient electroactive shape memory effect, shape reprogrammability, and self-healing. They exhibit electroactive shape memory behavior with recovery ratios of about 0.9; requiring less than a minute for shape recovery; electroactive self-healing behavior able to repair microcracks and almost fully recover their mechanical properties; requiring a voltage in the order of tens of volts for both shape memory and self-healing effects. To the best of our knowledge, this is the first report of electroactive self-healing shape memory polymer composites that use covalent reversible Diels–Alder linkages, which yield robust solvent-resistant polymer networks without jeopardizing their reprocessability. These responsive polymers may be ideal for soft robotics and actuators. They are also a step toward sustainable materials by allowing an increased lifetime of use and reprocessability.

Dynamic covalent polymer networks crosslinked through Diels–Alder (DA) reactions are promising self-healing, 3D-printable materials that have the unique ability to reshuffle their dynamic bonds in ...

An inverse-electron-demand Diels-Alder (IEDDA) reaction could complement the conventional normal-electron-demand Diels-Alder reaction in the synthesis of six-membered carbocycles. However, catalytic asymmetric all-carbon-based IEDDA reactions are underdeveloped. Herein, we disclosed a copper-catalyzed asymmetric IEDDA reaction using electron-deficient 3-carboalkoxyl-2-pyrones and electronically unbiased indenes as reactants. This method enables the rapid and enantioselective construction of a wide range of hexahydrofluorenyl bridged-lactone scaffolds. Using this method, asymmetric total syntheses of cephanolides A and B were accomplished.

The oxidation of diethyl 1,2-hydrazinedicarboxylate using a catalytic Cu(II)-oxazoline system occurs at RT in air, resulting in azo generation, which can then be trapped in situ via hetero-Diels-Alder (HDA) and competitive ene-reactions, with chemoselectivity being both temperature and solvent dependent. The procedure was extended to other azo systems and mechanism studies are reported.

An efficient and simple method for the synthesis of novel highly functionalized 1,4-dihydropyridines via a one-pot three-component reaction of 2-aminobenzothiazole, aryl aldehydes and Meldrum’s aci...

The development of bio-based polymers displaying promising end-of-life opportunities would have an immense impact on the polymer industry but has remained largely unexplored. Therefore, in this work, self-healing bio-aromatic networks with lignin contents up to 29 wt % were designed based on the thermoreversible Diels−Alder reaction. The networks were developed by reacting a furan-functionalized solvent-extracted lignin and a furan-bearing polyether (F5000) with a bismaleimide (DPBM). The obtained networks were nanophase-separated between a flexible F5000-rich phase and a rigid lignin-rich phase, which was evidenced by (modulated temperature) differential scanning calorimetry and small angle X-ray scattering. Partially due to the phase-separation, improved mechanical properties were obtained, including a higher Young’s modulus and improved toughness. In addition, the thermal stability of the networks significantly increased due to the addition of lignin. Besides the thermomechanical improvement, the networks showed promising stress-relaxation, creep resistance, healing, and reprocessability. A macroscopic healing efficiency of 62% of the toughness was obtained. Moreover, the networks were completely resoluble, which allows for promising recycling possibilities.

In this work, NH2-substituted oxazoles and NO2/NF2/NHNO2-substituted ethylenes/acetylenes were designed and used as dienes and dienophiles, respectively, in order to develop new bridge-ring insensitive high energy compounds through the Diels-Alder reaction between them. The reaction type, reaction feasibility and performance of reaction products were investigated in detail theoretically. The results showed that dienes most possibly react with dienophiles through the HOMO-diene controlled normal Diels-Alder reaction at relatively low energy barrier. Tetranitroethylene could react with the designed dienes much more easily than other dienophiles, and was employed to further design 29 new bridge-ring energetic compounds. Due to high heat of formation, density and oxygen balance, all designed bridge-ring energetic compounds have outstanding detonation performance, 16 of them have higher energy than HMX (1,3,5,7-tetranitro-1,3,5,7-tetrazocine) and 2 others even possess comparative energy with the representative of high energy compounds CL-20 (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane). The predicted average h50 value of these bridge-ring energetic compounds is 83 cm, showing their low impact sensitivity. The NH2 groups could obviously impel the proceeding of Diels-Alder reactions, but would slightly decrease the energy and sensitivity performance. In all, the new designed bridge-ring compounds have both high energy and low sensitivity, and may be produced through Diels-Alder reactions at relatively low energy barrier. This paper may be helpful for the theoretical design and experiment synthesis of new advanced insensitive high energy compounds.

In the present article, a DFT approach is used at the M06-2X/6-311G((d,p)) level of theory to survey [2+4] Diels—Alder cycloaddition reactions of anthracene with C2X2 (X = H, F, Cl, Me). To illustrate the interaction between two fragments in transition states and products, the energy decomposition analysis is employed. The stability of two feasible products are contrasted. The substituent impact barrier height (ΔE‡) and thermodynamic parameters (ΔG‡ and ΔH‡) of this reaction are found. To check the advancement of the reactions, Wiberg bond indices are applied. Furthermore, the synchronicity values of this reaction are identified.

Triazines are an important class of six-membered aromatic heterocycles possessing three nitrogen atoms, resulting in three types of regio-isomers: 1,2,4-triazines (a-triazines), 1,2,3-triazines (v-triazines), and 1,3,5-triazines (s-triazines). Notably, the application of triazines as cyclic aza-dienes in inverse electron-demand Diels-Alder (IEDDA) cycloaddition reactions has been established as a unique and powerful method in N-heterocycle synthesis, natural product preparation, and bioorthogonal chemistry. In this review, we comprehensively summarize the advances in the construction of these triazines via annulation and ring-expansion reactions, especially emphasizing recent developments and challenges. The synthetic transformations of triazines are focused on IEDDA cycloaddition reactions, which have allowed access to a wide scope of heterocycles, including pyridines, carbolines, azepines, pyridazines, pyrazines, and pyrimidines. The utilization of triazine IEDDA reactions as key steps in natural product synthesis is also discussed. More importantly, a particular attention is paid on the bioorthogonal application of triazines in fast click ligation with various strained alkenes and alkynes, which opens a new opportunity for studying biomolecules in chemical biology.

Asynchronicity in Diels–Alder reactions plays a crucial role in determining the height of the reaction barrier. Currently, the origin of asynchronicity is ascribed to the stronger orbital interaction between the diene and the terminal carbon of an asymmetric dienophile, which shortens the corresponding newly formed C–C bond and hence induces asynchronicity in the reaction. Here, we show, using the activation strain model and Kohn–Sham molecular orbital theory at ZORA-BP86/TZ2P, that this rationale behind asynchronicity is incorrect. We, in fact, found that following a more asynchronous reaction mode costs favorable HOMO–LUMO orbital overlap and, therefore, weakens (not strengthens) these orbital interactions. Instead, it is the Pauli repulsion that induces asynchronicity in Diels–Alder reactions. An asynchronous reaction pathway also lowers repulsive occupied–occupied orbital overlap which, therefore, reduces the unfavorable Pauli repulsion. As soon as this mechanism of reducing Pauli repulsion dominates, the reaction begins to deviate from synchronicity and adopts an asynchronous mode. The eventual degree of asynchronicity, as observed in the transition state of a Diels–Alder reaction, is ultimately achieved when the gain in stability, as a response to the reduced Pauli repulsion, balances with the loss of favorable orbital interactions., Quantum chemical activation strain analyses reveal that asynchronicity in Diels–Alder reactions reduces both destabilizing Pauli repulsion as well as stabilizing orbital interactions, and occurs if the former dominates.

Epoxy-polyhedral oligomeric silsesquioxane (POSS) nanocomposites were prepared by incorporating POSS nanofiller into the epoxy-amine network. The monofunctional epoxy-POSS monomer or nonfunctional ...

For a long time, allenes—and cumulenic systems in general—played a relatively minor role in Diels–Alder cycloadditions. This situation has changed, since allenes are more readily available and as their unique stereochemical features in [4+2]cycloadditions are more widely recognized. This review presents a comprehensive overview of allenes in Diels–Alder processes using selected examples. Allenes in dienes, dienophiles and cycloadducts are covered, inter- and intramolecular Diels–Alder cycloadditions are discussed, and stereochemical features of the addition process are described. Areas of emerging importance are also covered, including allenic components in dehydro-Diels–Alder processes, and dendralenic allenes in Diels–Alder sequences for the rapid generation of target-relevant molecular complexity. Preparatively useful methods for allenic precursor synthesis are also discussed.1 Introduction2 Allenic Dienes2.1 Vinylallenes2.2 Bisallenes2.3 Cross-conjugated Allenes3 Allenic Dienophiles4 Intramolecular Diels–Alder Cycloadditions5 Allenic Cycloadducts6 Conclusions and Outlook

The thermosetting polyurea possessed high tensile strength and elongations at break due to strong intermolecular interactions, but their recycling and reprocessing remains a great challenge, especially at a temperature below 100 °C. Herein, the novel crosslinked polyurea with excellent recycling and reprocessing properties has been prepared by introducing the Diels-Alder dynamic covalent bond. The chemical structure, thermal mechanical properties and reprocessing performance of the crosslinked polyurea were investigated. The prepared polyurea has low relaxation time of ∼4 min at 80 °C for facile reprocessing. The tensile strength and elongation at break of crosslinked polyurea could reach 15.24 MPa and 529.2%, respectively, and its mechanical properties remain almost unchanged even after repeated processing. This work has realized the recycling of crosslinked polyurea, which has huge potential applications in environmental protection and recycling of waste plastics.

The 1,2,3-triazole-fused polyaromatic frameworks are traditionally obtained through transition metal-catalyzed C-H/C-X arylation of the preinstalled triazoles at a very high temperature. Herein, a transition metal-free direct synthesis via an aryne Diels-Alder/1,3-prototropic shift/dehydrobromination cascade is reported. This method gives access to triazole-fused aromatics as well as the corresponding dihydrocarbocycles under mild reaction conditions.

Anionic Diels-Alder chemistry of electron-deficient cross-conjugated vinylogous alkenones, providing highly stable sodium dienolate ion pairs as electron-rich dienes in the presence of a weak sodium base in THF, has been newly developed, leading to a single Diels-Alder adduct, in racemic form, in moderate to high yields (up to 97%, 37 examples).

A highly efficient visible light mediated photochemical [2+2] cycloaddition is coupled with an atom economic thermal cascade reaction in a continuous flow process. By moving the photochemistry from UV to visible it is made more energy efficient and can be conducted with readily available equipment. The application of high-temperature flow chemistry to the thermal cascade step allows for safe and reliable scale-up with short reaction times. Thus, we demonstrate a rare example of a photo/thermal daisy-chained process and, specifically, the first visible light mediated excited state to thermal cascade reaction as a fully continuous process (20 g/h). The synthetic utility of flow chemistry is further showcased by the isolation of a reactive intermediate at quantities not possible under batch conditions.

The solid-state cultivation of Acaulium sp. H-JQSF isolated from Armadillidium vulgare produces acautalides A-C (1-3) as skeletally unprecedented Diels-Alder adducts of a 14-membered macrodiolide to an octadeca-9,11,13-trienoic acid. The acautalide structures, along with the intramolecular transesterifications of 1-acylglycerols, were elucidated by mass spectrometry, nuclear magnetic resonance, chemical transformation, and single-crystal X-ray diffraction. Compounds 1-3 were found to be neuroprotective with antiparkinsonic potential in the 1-methyl-4-phenylpyridinium-challenged nematode model, with the magnitude impacted by the glycerol esterification.

A highly regioselective method was developed for the preparation of pyridazine derivatives via the aza-Diels-Alder reaction of 1,2,3-triazines with 1-propynylamines under neutral conditions. This methodology allowed direct access to a wide range of 6-aryl-pyridazin-3-amines in high yields with good functional group compatibility. Key features of this strategy included a broad substrate scope and simple, metal-free, and neutral reaction conditions.

The enantioselective synthesis of axially chiral biaryls by a copper-catalyzed Diels-Alder/retro-Diels-Alder reaction of 2-pyrones with alkynes is reported herein. Using electron-deficient 2-pyrones and electron-rich 1-naphthyl acetylenes as the reaction partners, a broad range of axially chiral biaryl esters are obtained in excellent yields (up to 97% yield) and enantioselectivities (up to >99% ee). DFT calculations reveal the reaction mechanism and provide insights into the origins of the stereoselectivities. The practicality and robustness of this reaction are showcased by gram-scale synthesis. The synthetic utilizations are demonstrated by the amenable transformations of the products.

Mechanochemistry is an emerging field with many potential applications in sustainable chemistry. But despite the growing interest in the field, its underlying mechanistic foundations are not fully understood yet. This work presents the application of computational tools, such as DFT calculations in continuum and microkinetic modeling, to the analysis of mechanically activated procedures. Two reactions reported in previous experimental publications were studied: (i) a series of Diels-Alder reactions and (ii) the synthesis of sulfonylguanidines. Calculations succeed in reproducing experimentally reported reaction times. The procedures were mostly standard, coupled with some sensitive choices in terms of starting concentrations and dielectric constant. This means that these particular reactions accelerated by ball milling followed the same mechanism as the equivalent reactions in solution. The implications of this result on the general picture of mechanochemical processes are discussed.

We reports a novel thermally enhanced drug release system synthesized via a dynamic Diels-Alder (DA) reaction to develop chemotherapy for pancreatic cancer. The anticancer prodrug was designed by tethering gemcitabine (GEM) to poly(furfuryl methacrylate) (PFMA) via N-(3-maleimidopropionyloxy)succinimide as a linker by DA reaction (PFMA-L-GEM). The conversion rate of the DA reaction was found to be approximately 60% at room temperature for 120 h. The reversible deconstruction of the DA covalent bond in retro Diels-Alder (rDA) reaction was confirmed by proton nuclear magnetic resonance, and the reaction was significantly accelerated at 90 °C. A PFMA-LGEM film containing magnetic nanoparticles (MNPs) was prepared for thermally enhanced release of the drug via the rDA reaction. Drug release was initiated by heating MNPs by alternating magnetic field. This enables local heating within the film above the rDA reaction temperature while maintaining a constant surrounding medium temperature. The MNPs/PFMA-L-GEM film decreased the viability of pancreatic cancer cells by 49% over 24 h. Our results suggest that DA/rDA-based thermally enhanced drug release systems can serve as a local drug release platform and deliver the target drug within locally heated tissue, thereby improving the therapeutic efficiency and overcoming the side effects of conventional drugs used to treat pancreatic cancer., Graphical abstract

Melt blowing is a process in which liquid polymer is extruded through orifices and then drawn by hot air jets to produce nonwoven fibers with average diameters typically greater than one micron. Melt-blown nonwoven fiber products constitute a significant fraction (i.e., more than 10%) of the $50 billion global nonwovens market. Thermoplastic feedstocks, such as polyethylene, polypropylene, poly(phenylene sulfide), and poly(butylene terephthalate), have dominated melt-blown nonwovens because of their combined cost, good chemical resistance, and high-temperature performance. Cross-linked nonwovens from other commodity polymers (e.g., (meth)acrylates, styrenics, silicones, etc.) could be attractive alternatives; however, no commercial cross-linked nonwovens currently exist. Here, cross-linked fibers were produced via one-step melt blowing of thermoreversible Diels-Alder polymer networks comprised of furan- and maleimide-functional methacrylate-based polymer backbones. These dynamic networks de-cross-link and flow like viscous liquids under melt-blowing conditions and then revert to a network via cooling-induced cross-linking during/after melt blowing. Finally, the resulting cross-linked fibers can be recycled after use because of their reversible dynamic nature, which may help address microfiber waste as a significant source of microplastic pollution.

The oxa-Diels–Alder reaction is a straightforward, atom-economical process for the construction of six-membered oxacycles, which are privileged structures due to their very common occurrence in several pharmaceuticals and natural products. As with many other asymmetric transformations, organocatalysis provides an elegant pathway to their synthesis via [4+2] annulation under mild reaction conditions. The oxa-Diels–Alder reaction utilizes either an α,β-unsaturated carbonyl as an oxa-diene with a suitable dienophile or a simple carbonyl as a dienophile with other dienes. A range of organocatalysts has been explored in the past decade to execute this strategy. The catalysts induce stereoselectivities via two basic reactivities: (1) The formation of chiral intermediates, or (2) selectively activating suitable reactants via a transition state. The present short review compiles organocatalyzed asymmetric oxa-Diels–Alder reactions published over the last ten years, along with detailed discussions on mechanistic approaches.1 Introduction2 Catalysis through Covalent Activation2.1 N-Heterocyclic Carbenes2.2 Amines2.3 Isothiourea Catalysis2.4 Phosphines3 Catalysis through Non-Covalent Activation3.1 Bifunctional Amines3.2 Brønsted Acids3.3 Guanidines4 Multicatalysis through Both Covalent and Non-Covalent Activation5 Conclusion

A solvent-free and easy method to directly functionalize pristine graphene by maleic anhydride (MA) based on Diels-Alder cycloaddition reaction was reported. Functionalized graphene/Polyamide 66 (F...

Since the discovery of left-handed G-quadruplex (L-G4) structure formed by natural DNA, there has been a growing interest in its potential functions. This study utilised it to catalyse enantioselective Diels-Alder reactions, considering its different optical rotation compared to an ordinary G4. It was determined that when L-G4 was used with a combination of copper(II) ions, there was a good enantioselectivity (−52% ee) without further addition of ligands. When further consideration was given by adding G4 ligands, G4 was further stabilised, even obtaining a better enantioselectivity (up to −80% ee). Moreover, when using ligands that have regulatory effects on G4, the ee value can be adjusted. In this work, a minimal left-handed G4 was reported. A follow-up study was also conducted, which recovers that the minimal left-handed G4 remains its catalytic effect and enantioselectivity, but is not so effective as the former case. This indicates that a complete G4 structure is relatively conducive to chiral catalysis.

8-Hydroxy(methoxy)-substituted 2-[6-(1-methylindol-3-yl)pyridin-2-yl]quinoline ligands were synthesized by means of combination of SNH reaction between 8-methoxy-substituted 2-(6-aryl-1,2,4-triazin-3-yl)quinolones and indole and aza-Diels–Alder reaction of the obtained 1,2,4-triazines with 2,5-norbornadiene. The demethylation of quinoline moiety of 1,2,4-triazine precursor during aza-Diels–Alder reaction in autoclave was demonstrated.

The recyclability of thermoreversibly Diels–Alder (DA) crosslinked EPM has been studied. The retro DA reaction dominates over the dehydration–aromatization process of the DA adduct. Moreover, a negative influence of air occurred as a result of a crosslinking in air flow. Nevertheless, rubber compounds prepared from EPM-g-furan and carbon black can be recycled several times without losing mechanical strength, a feature attributed to a strong antioxidant effect of the carbon black.

The large and significant increase in carbon dioxide concentration in the Earth’s atmosphere is a serious problem for humanity. The amount of CO2 is increasing steadily which causes a harmful greenhouse effect that damages the Earth’s climate. Therefore, one of the current trends in modern chemistry and chemical technology are issues related to its utilization. This work includes the analysis of the possibility of chemical consumption of CO2 in Diels-Alder processes under non-catalytic and catalytic conditions after prior activation of the C=O bond. In addition to the obvious benefits associated with CO2 utilization, such processes open up the possibility of universal synthesis of a wide range of internal carboxylates. These studies have been performed in the framework of Molecular Electron Density Theory as a modern view of the chemical reactivity. It has been found, that explored DA reactions catalyzed by Lewis acids with the boron core, proceeds via unique stepwise mechanism with the zwitterionic intermediate. Bonding Evolution Theory (BET) analysis of the molecular mechanism associated with the DA reaction between cyclopentadiene and carbon dioxide indicates that it takes place thorough a two-stage one-step mechanism, which is initialized by formation of C–C single bond. In turn, the DA reaction between cyclopentadiene and carbon dioxide catalysed by BH3 extends in the environment of DCM, indicates that it takes place through a two-step mechanism. First path of catalysed DA reaction is characterized by 10 different phases, while the second by eight topologically different phases.

This comprehensive review focuses on the different synthetic approaches to various heterocycles by means of oxazole-olefin intramolecular Diels–Alder reactions (DARs), which include multicomponent ...

Mulberry Diels-Alder-type adducts (MDAAs) are a group of rare natural polyphenols biosynthetically derived from [4 + 2]-cycloaddition of chalcones and dehydroprenylphenols. In this study, kuwanons G (1) and H (2), two bioactive MDAAs with unique dehydroprenylflavonoid dienes, were totally synthesized for the first time in a biomimetic manner. The key features of the convergent route include the use of the Baker-Venkataraman rearrangement, alkylation of β-diketone, intramolecular cyclization, and Suzuki-Miyaura coupling to achieve the subunit diene.

We describe two complementary approaches based on a convergent [4+2] logic toward the synthesis of amorfrutins, cannabinoids, and related plant metabolites. An anionic cascade cyclization employing β-methoxycrotonates and β-chloro-α,β-unsaturated esters yielded amorfrutins in four linear steps and demonstrated utility of β-alkoxycrotonate-derived nucleophiles as functional equivalents of β-ketoester-derived dianions. Analogously, tandem Diels-Alder/retro-Diels-Alder cycloaddition of dimedone-derived bis(trimethylsiloxy)-dienes and α,β-alkynyl ester dienophiles provided facile access to resorcinol precursors of amorfrutins and cannabinoids, avoiding late-stage installation of prenyl or geranyl moieties as in previous approaches.