Diels-Alder Research Articles

Dynamic covalent polymer network enabled bio‐based vitrimers with excellent substrate bonding

AbstractIn this article, we report the synthesis of dynamic covalent polymer network (DCPN)‐enabled vitrimers derived from gum rosin—a pine tree extract. The concept of Diels Alder (DA) thermo‐reversibility has been used to introduce self‐healing/dynamic covalent ability into the polymer systems. For this purpose, the diene moieties were incorporated in the gum rosin‐based polymer network, and the bismaleimides served as the dienophiles. The thermo‐reversible crosslinks formed between the diene and dienophile moieties can enhance the service life of the materials by improving the durability, mechanical as well as chemical properties of the materials. Upon damage, the thermo‐reversible DA bonds de‐crosslink resulting in smaller chain segments, enabling the material to flow to the site of damage and seal the fractured edges. The formation of DA crosslinks has been confirmed by using Fourier transform‐infrared spectroscopic technique. Scanning electron microscopy analysis was used to verify the self‐healing ability of the resin matrix. The healing process was studied after manual scratches were made. The polymers' ability to heal multiple times is investigated using differential scanning calorimetry. The adhesion strength of the self‐healing material has been examined on variety of substrates such as glass, steel, and concrete. The materials exhibited superior adhesion strength on glass substrate.

Bioorthogonal Cycloadditions of C3-Trifluoromethylated 1,2,4-Triazines with trans-Cyclooctenes.

1,2,4-triazines are a valuable class of heterodienes that can be employed in inverse electron-demand Diels-Alder reactions. However, their broader application in bioorthogonal chemistry is limited due to their low reactivity. This article focuses on 3-(trifluoromethyl)-1,2,4-triazines, which can be efficiently prepared in a one-pot reaction from NH-1,2,3-triazoles. These triazines are highly reactive in reactions with strained cyclooctenes, giving second-order rate constants as high as 230 M-1 s-1. Despite their high reactivity, the compounds remain sufficiently stable under biologically relevant conditions. We show that some of the compounds are fluorogenic, a property of potential use in bioimaging. In addition, we demonstrate the successful application of the triazines in labeling model biomolecules. Our work shows that the reactivity of 1,2,4-triazines can be enhanced by the 3-CF3-substitution, which we consider an important step toward the wider use of this promising class of reagents.

Chiral twisted molecular carbons: Synthesis, properties, and applications

AbstractIn recent years, the precisely controlled synthesis of chiral twisted molecular carbons has emerged as a forefront topic in the research of carbon materials. Molecular carbons refer to carbon nanomaterials synthesized with precision at the atomic level. Through rational design, rigid and stable chiral twisted structures can be synthesized. The exploration in the field of chiral twisted molecular carbons is key to fully understanding the various twisted configurations of carbon materials and delving into the relationship between structure design and functionality. This review explores chiral twisted configurations of carbon nanomaterials such as nanographene, carbon nanobelts, carbon nanosheets, graphdiyne, etc. It emphasizes the role of photocyclization, Scholl reaction, and Diels–Alder reactions in achieving precise chiral control and discusses a range of innovative design strategies. These strategies have led to the development of various twisted structures, such as helical, propeller, and Möbius strip configurations. The introduction of chirality, combined with the inherent exceptional optical properties of nanocarbon materials, has facilitated the creation of materials with superior chiroptical performances. This advancement is driving applications in fields such as optoelectronics and chiral optics.

Coherence mapping to identify the intermediates of multi-channel dissociative ionization

Identifying the short-lived intermediates and reaction mechanisms of multi-channel radical cation fragmentation processes remains a current and important challenge to understanding and predicting mass spectra. We find that coherent oscillations in the femtosecond time-dependent yields of several product ions following ultrafast strong-field ionization represent spectroscopic signatures that elucidate their mechanism of formation and identify the intermediate(s) they originate from. Experiments on endo-dicyclopentadiene show that vibrational frequencies from various intermediates are mapped onto their resulting products. Aided by ab initio methods, we identify the vibrational modes of both the cleaved and intact molecular ion intermediates. These results confirm stepwise and concerted fragmentation pathways of the dicyclopentadiene ion. This study highlights the power of tracking the femtosecond dynamics of all product ions simultaneously and sheds further light onto one of the fundamental reaction mechanisms in mass spectrometry, the retro-Diels Alder reaction.

Confinement as a Tool in Chemistry: Accelerated Intracapsular Dimerization of Cyclopentadiene in Water

AbstractIn this study, the occurrence of Diels–Alder reaction of cyclopentadiene yielding dicyclopentadiene within a confined closed space provided by octa acid (OA) in water at room temperature is established. The Diels–Alder reaction within the OA capsule occurs at least 2000 times faster than in water. Catalysis of Diels–Alder reaction by hosts such as cyclodextrin, cucurbituril, and Fujita's Pd nano–host occurs in water. Despite their similarity, these three hosts provide an open environment where the reactant molecules are exposed to aqueous environment. The only fully closed host known to catalyze the Diels–Alder reaction in water is OA. Although Rebek's host is established to catalyze Diels–Alder reaction it occurs in an organic solvent. The closed environment explored in this presentation provides an opportunity to better understand the origin of non–covalent catalysis in a restricted space and in water. Because the product binds stronger than the reactant, disappointingly, the capsule can't be recycled. We recognize that this aspect needs to be addressed for the OA capsule to become synthetically useful. We are in the process of understanding the origin of catalysis and finding ways to make reaction recyclable.

Weak Interaction Activates Esters: Reconciling Catalytic Activity and Turnover Contradiction by Tailored Chalcogen Bonding.

The activation of esters by strong Lewis acids via the formation of covalent adducts is a classic strategy to give reactivity; however, this approach frequently incurs limited turnover due to the low efficiency in the dissociation of catalyst from a stable catalyst-product complex. While the use of some weak interaction catalysts that can easily dissociate from any bonding complexes in the reaction system would solve this catalyst turnover problem, the poor catalytic activity in the ester activation that can be provided by these noncovalent forces in turn sets up a formidable challenge. Herein, we describe the activation and catalytic transformation of esters by weak interactions, which provides a promising platform to reconcile the catalytic activity and turnover problems. Several tailored chalcogen-bonding catalysts were developed for the activation of esters, enabling achieving several inherently low reactive Diels-Alder reactions as well as the ring-opening polymerization of lactones through weak chalcogen bonding interactions. This supramolecular catalysis approach is particularly highlighted by its capability to promote some uncommon Diels-Alder reactions involving using dienes bearing electron-withdrawing groups coupled by α,β-unsaturated ester as dienophiles and substrate incorporating competitive Lewis basic sites, in which typical strong Lewis acids showed low catalytic efficiency, while representative hydrogen and halogen bonding catalysts were inactive.

Controlled In Situ Self-Assembly of Biotinylated Trans-Cyclooctene Nanoparticles for Orthogonal Dual-Pretargeted Near-Infrared Fluorescence and Magnetic Resonance Imaging.

A pretargeted strategy that decouples targeting vectors from radionuclides has shown promise for nuclear imaging and/or therapy in vivo. However, the current pretargeted approach relies on the use of antibodies or nanoparticles as the targeting vectors, which may be compromised by poor tissue penetration and limited accumulation of targeting vectors in the tumor tissues. Herein, we present an orthogonal dual-pretargeted approach by combining stimuli-triggered in situ self-assembly strategy with fast inverse electron demand Diels-Alder (IEDDA) reaction and strong biotin-streptavidin (SA) interaction for near-infrared fluorescence (NIR FL) and magnetic resonance (MR) imaging of tumors. This approach uses a small-molecule probe (P-Cy-TCO&Bio) containing both biotin and trans-cyclooctene (TCO) as a tumor-targeting vector. P-Cy-TCO&Bio can efficiently penetrate subcutaneous HeLa tumors through biotin-assisted targeted delivery and undergo in situ self-assembly to form biotinylated TCO-bearing nanoparticles (Cy-TCO&Bio NPs) on tumor cell membranes. Cy-TCO&Bio NPs exhibited an "off-on" NIR FL and retained in the tumors, offering a high density of TCO and biotin groups for the concurrent capture of Gd-chelate-labeled tetrazine (Tz-Gd) and IR780-labeled SA (SA-780) via the orthogonal IEDDA reaction and SA-biotin interaction. Moreover, Cy-TCO&Bio NPs offered multiple-valent binding modes toward SA, which additionally regulated the cross-linking of Cy-Gd&Bio NPs into microparticles (Cy-Gd&Bio/SA MPs). This process could significantly (1) increase r1 relaxivity and (2) enhance the accumulation of Tz-Gd and SA-780 in the tumors, resulting in strong NIR FL, bright MR contrast, and an extended time window for the clear and precise imaging of HeLa tumors.

Competing Domino Knoevenagel-Cyclization Sequences with N-Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of N-arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the N-vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC50 values was identified for some of the novel scaffolds.

Castor oil-based polyurethane Vitrimer modified asphalts regulated by dual dynamic reversible reactions and crosslinking density: Preparation, basic assessment and self-healing behavior

Thermosetting polymers, commonly used to improve asphalt properties, bring excellent pavement performance, but also pose significant challenges to the healing and recyclability of their modified asphalts after long-term service. An effective approach involves introducing dynamic bonds into the crosslinking networks to synthesize Vitrimer-modified asphalts with self-healing response. Due to the splendid mechanical properties, high elasticity, flexibility and easily controllable cross-linked structure of polyurethane, a novel castor oil-based polyurethane Vitrimer modified asphalt with disulfide bonds and Diels-Alder reactions was developed. Based on the prepared castor oil-based polyurethane Vitrimer (C-PUV, composed of components A and B) and its modified asphalts (C-PUVAs), a comprehensive study was conducted on the crosslinking density, mechanical properties, thermal stability, viscosity, compatibility, rheological properties, and self-healing behavior. The results indicated that C-PUVAs (C-PUVA1/C-PUVA2/C-PUVA3/C-PUVA4) exhibited sufficient retention times for viscosity, uniform phase distribution, and good high-temperature performance. The damaged C-PUVAs achieved a mechanical strength recovery rate more than 75 % after the first cycle of self-healing at 80 ℃ and 0.3 MPa. Furthermore, the crosslinking density of C-PUV was regulated by the segment length of component B. As the crosslinking density increased, C-PUV and C-PUVAs obtained higher mechanical strength while sacrificing part of self-healing efficiency. The mechanism is that increased crosslinking density altered the gel point distributions of the reversible crosslinked networks, resulting in a longer relaxation time and higher activation energy. In conclusion, the above findings provided valuable insights for developing bio-based polyurethane Vitrimer modified asphalts, and endosing thermosetting polymer modified asphalts with self-healing and recyclable properties.

Synthesis of chlorophyll–quinone conjugates by Diels–Alder reaction and their fluorescence quenching by intramolecular electron transfer

Methyl pyropheophorbides-a possessing a 1,4-naphthoquinon-5-yl or 9,10-anthraquinon-1-yl group at the 3-position were prepared by the Diels–Alder reaction of 3-(1,3-butadienyl)chlorin with benzoquinone or naphthoquinone and successive dehydrogenative oxidation. The synthetic chlorophyll-a derivatives directly bonded with the quinone were atropisomers around the C3–C31 bond, which were readily separated by HPLC. Since the quinone moiety was nearly perpendicular to the chlorin π-system, the distance and orientation between the chlorin and quinone chromophores were fixed in a molecule. The visible absorption spectra of the synthetic chlorin–quinone conjugates were independent of the quinone part and the axial chirality. Their fluorescence emissions were almost completely quenched by intramolecular electron transfer from the photoexcited chlorin to the quinone, which resembled the charge-separating process in photosynthetic reaction centers.

Highly Stereoselective Diels-Alder-Based Strategy for the Synthesis of 3-epi-Formicin A and 1-epi-Formicin B.

The first enantioselective approach based on a highly stereoselective Diels-Alder reaction for the synthesis of 3-epi-formicin A and 1-epi-formicin B with rare N-acetylcysteamine-containing indenone thioesters is reported. The strategy utilizes a key Diels-Alder reaction to form the core hydrindane system with three contiguous stereocenters in very high levels of diastereo- and regioselectivity and one-pot oxidation/isomerization/dehydrogenation. The scope of this method was tested with different substrates to give cycloadducts in a highly diastereoselective manner.

Bispericyclic Ambimodal Dimerization of Pentafulvene: The Origin of Asynchronicity and Kinetic Selectivity of the Endo Transition State.

The propensity of fulvenes to undergo dimerization has long been known, although the in-depth mechanism and electronic behavior during dimerization are still elusive. Herein, we made an attempt to gain insights into the reactivity of pentafulvene for Diels-Alder (DA) and [6 + 4]-cycloadditions via conventional and ambimodal routes. The result emphasizes that pentafulvene dimerization preferentially proceeds through a unique bifurcation mechanism where two DA pathways merge together to produce two degenerate [4 + 2]-cycloadducts from a single TS. Despite the [6 + 4]-cycloadduct being thermodynamically preferred, [4 + 2]-cycloaddition reactions are kinetically driven. Singlet biradicaloid is involved in through-space 6e- delocalization as a secondary orbital interaction that originates asynchronicity and stabilizes the bispericyclic transition state (TS). The transformation of various actively participating intrinsic bonding orbitals (IBOs) unambiguously forecasts the formation of multiple products from a single TS and rationalizes the mechanism of ambimodal reactions that are rather difficult to probe with other analyses. The changes in active IBOs clearly distinguish the conventional reactions from bifurcation reactions and can be employed to characterize and confirm the ambimodal mechanism. This report gains a crucial theoretical insight into the mechanism of bifurcation, the origin of asynchronicity, and electronic behavior in ambimodal TS, which will certainly be of enormous value for future studies.

Broadening the Utility of Farnesyltransferase-Catalyzed Protein Labeling Using Norbornene-Tetrazine Click Chemistry.

Bioorthogonal chemistry has gained widespread use in the study of many biological systems of interest, including protein prenylation. Prenylation is a post-translational modification, in which one or two 15- or 20-carbon isoprenoid chains are transferred onto cysteine residues near the C-terminus of a target protein. The three main enzymes─protein farnesyltransferase (FTase), geranylgeranyl transferase I (GGTase I), and geranylgeranyl transferase II (GGTase II)─that catalyze this process have been shown to tolerate numerous structural modifications in the isoprenoid substrate. This feature has previously been exploited to transfer an array of farnesyl diphosphate analogues with a range of functionalities, including an alkyne-containing analogue for copper-catalyzed bioconjugation reactions. Reported here is the synthesis of an analogue of the isoprenoid substrate embedded with norbornene functionality (C10NorOPP) that can be used for an array of applications, ranging from metabolic labeling to selective protein modification. The probe was synthesized in seven steps with an overall yield of 7% and underwent an inverse electron demand Diels-Alder (IEDDA) reaction with tetrazine-containing tags, allowing for copper-free labeling of proteins. The use of C10NorOPP for the study of prenylation was explored in the metabolic labeling of prenylated proteins in HeLa, COS-7, and astrocyte cells. Furthermore, in HeLa cells, these modified prenylated proteins were identified and quantified using label-free quantification (LFQ) proteomics with 25 enriched prenylated proteins. Additionally, the unique chemistry of C10NorOPP was utilized for the construction of a multiprotein-polymer conjugate for the targeted labeling of cancer cells. That construct was prepared using a combination of norbornene-tetrazine conjugation and azide-alkyne cycloaddition, highlighting the utility of the additional degree of orthogonality for the facile assembly of new protein conjugates with novel structures and functions.

Synthetic Approach toward Diverse Oxa-Cages via Olefin Metathesis.

This article demonstrates a late-stage modification of the cage propellanes that are transformed into intricate oxa-cycles via ring-rearrangement metathesis (RRM) and regioselective ring-closing metathesis (RCM) as crucial steps. In addition, we also report the extended pentacycloundecane (PCUD)-based oxa-cages involving the domino cycloetherification followed by olefin metathesis. These oxa-cages involve a domino sequence in which the PCUD core unit remains intact. [Ru]-based Grubbs catalysts are used to execute the metathesis step to assemble these higher-order oxa-cage systems. Spectroscopic data assigned structures of various products and were further supported by single-crystal X-ray diffraction analysis. The synthetic approach to these cage polycycles involves high complexity generating processes such as Diels-Alder reaction, [2 + 2] photocycloaddition, and RRM as well as RCM.

Recycling development and shaping of a thermo-reversible epoxy resin with partial contents of Diels-Alder bonds

Thermo-mechanical recycling and reshaping of dynamic covalent networks is a promising field under development that could help to increase thermoset sustainability. Herein, the reprocessing of a partially reversible epoxy resin with a 0.6 Diels-Alder crosslink ratio, which has a relatively high Tg and a simplified manufacturing route, is studied to determine the optimal conditions for its thermomechanical recycling through milling and hot-pressing, and reshaping. Thus, in this work, we have studied the influence of compaction time, pressure, and temperature on recycled bulk properties. Meanwhile, different heating temperatures and times are also tested to evaluate the cured resin shaping to fix a new geometry and to observe its shape-recovering capability. Their characterization reveals that the recycling method generates dense thermosetting polymers with similar crosslinking structure and behavior, comparable to the virgin resin, inducing light post-curing that increases their glass transition temperature (Tg). The most efficient thermo-mechanical recycling conditions consist of the application of isothermal compaction at 130 °C and 150 bar for 30 min, which leads to resin bulks with comparable properties to the neat resin even after 3 cycles of milling and hot-pressing. On the other hand, the synthesized resin has shown excellent shaping due to the structural relaxation induced by the initiation of retro Diels-Alder reaction, adopting new geometries easily when the samples are heated above their Tg (91 °C) and preserving them after cooling to ambient temperature. Moreover, the samples also show high shape-recovering after heating again up to Tg. This reshaping and recovery have been maintained for several cycles without observing an irreversible lack of shape fixing or shape recovery.

Synthesis of the A/D/E-ring Core Compounds of Maoecrystal V.

Synthesis of the A/D/E-ring core compounds of maoecrystal V was achieved. The key Diels-Alder reactions between tricyclic α-methylene lactones and Kitahara-Danishefsky dienes afforded the spirocyclic core compounds in a regioselective and stereoselective manner.

Room Temperature Diels-Alder Reactions of 4-Vinylimidazoles.

In the course of studying Diels-Alder reactions of 4-vinylimidazoles with N-phenylmaleimide, it was discovered that they engage in cycloaddition at room temperature to give high yields of the initial cycloadduct as a single stereoisomer. In certain cases, the product precipitated out of the reaction mixture and could be isolated by simple filtration, thereby avoiding issues with aromatization observed during chromatographic purification. Given these results, intramolecular variants using doubly activated dienophiles were also investigated at room temperature. Amides underwent cycloaddition at room temperature in modest yields, but the initial adducts were not isolable with Nimid-benzyl-protected systems. Attempts to extend these results to the corresponding esters and hydroxamate were less successful with these substrates only undergoing cycloaddition at elevated temperatures in lower yields. Density functional theory calculations were performed to evaluate the putative transition states for both the inter- and intramolecular variants to rationalize experimental observations.

Evaluation of Retro-Aldol vs Retro-Carbonyl-Ene Mechanistic Pathways in a Complexity-Generating C-C Bond Fragmentation.

We report an experimental and computational investigation of the likely mechanism of a cascade reaction. The reaction involves an intramolecular Diels-Alder reaction, followed by a C-C bond cleavage, to afford a complex bridged bicyclic product. As multiple reaction pathways could be envisioned for the latter step, the mechanism of the C-C bond cleavage step was investigated. Two reasonable reaction pathways were evaluated. Both computations and experiments indicate that the C-C bond cleavage step proceeds by a retro-carbonyl-ene pathway rather than a retro-aldol pathway. This report underscores the synergy between computational and experimental studies and establishes the mechanism of an interesting complexity-generating transformation.

Revealing the Critical Role of Global Electron Density Transfer in the Reaction Rate of Polar Organic Reactions within Molecular Electron Density Theory.

The critical role of global electron density transfer (GEDT) in increasing the reaction rate of polar organic reactions has been studied within the framework of Molecular Electron Density Theory (MEDT). To this end, the series of the polar Diels-Alder (P-DA) reactions of cyclopentadiene with cyanoethylene derivatives, for which experimental kinetic data are available, have been chosen. A complete linear correlation between the computed activation Gibbs free energies and the GEDT taking place at the polar transition state structures (TSs) is found; the higher the GEDT at the TS, the lower the activation Gibbs free energy. An interacting quantum atoms energy partitioning analysis allows for establishing a complete linear correlation between the electronic stabilization of the electrophilic ethylene frameworks and the GEDT taking place at the polar TSs. This finding supports Parr's proposal for the definition of the electrophilicity ω index. The present MEDT study establishes the critical role of the GEDT in the acceleration of polar reactions, since the electronic stabilization of the electrophilic framework with the electron density gain is greater than the destabilization of the nucleophilic one, making a net favorable electronic contribution to the decrease in the activation energy.

Effect of the U-Shaped Cavity of Conformationally Flexible Chiral Lewis-Acidic Boron-Based Catalysts in Multiselective Diels-Alder Reactions.

The effect of the U-shaped cavity of conformationally flexible chiral Lewis acidic boron-based catalysts in multiselective Diels-Alder reactions was investigated. The U-shaped catalysts can recognize substituents at the terminal acetylene moiety of propynal based on steric factors and can also recognize alkyne and alkene substrates based on the match/mismatch between the catalysts and substrates. Moreover, even in a mixture of different catalysts and substrates, the desired competitive reactions can proceed multiselectively. This proof-of-concept study should contribute to the development of artificial enzyme-like catalysis in vitro.