Alder Reaction Research Articles

Overcoming Thermodynamically Driven Retro‐Diels–Alder Reaction through a Cascade One‐Pot Process Exemplified for a Bio‐Based Platform Chemical

AbstractIn this contribution, we describe a new approach to apply thermodynamically unfavored reactions in synthetic chemistry and to integrate them in cascade processes. By means of a new developed procedure for multi‐step one‐pot syntheses, we succeeded in nearly completely converting a thermodynamically labile Diels–Alder adduct, which strongly tends to react back, to the target product with high conversion of >99 % and in excellent yield by coupling with a rapid subsequent hydrogenation reaction. In detail, the process is based on the use of a rotating reaction vessel to form a thin product film of the thermodynamically labile Diels–Alder product from 2‐methylfuran and maleic acid anhydride (as two bio‐based raw materials), which then slowly dissolves into solution and is immediately converted by hydrogenation to the target product. Such a combination of Diels–Alder reaction and hydrogenation in a sequential one‐pot process without by‐product formation enables the efficient production of the product, which represents a valuable bio‐based platform chemical. In addition, this process concept generally opens a perspective for the integration of thermodynamically unfavorable reaction steps in multi‐step one‐pot cascade processes while obtaining the desired target products in high yields.

A New Self-Healing Degradable Copolymer Based on Polylactide and Poly(p-dioxanone).

In this paper, the copolymerization of poly (p-dioxanone) (PPDO) and polylactide (PLA) was carried out via a Diels-Alder reaction to obtain a new biodegradable copolymer with self-healing abilities. By altering the molecular weights of PPDO and PLA precursors, a series of copolymers (DA2300, DA3200, DA4700 and DA5500) with various chain segment lengths were created. After verifying the structure and molecular weight by 1H NMR, FT-IR and GPC, the crystallization behavior, self-healing properties and degradation properties of the copolymers were evaluated by DSC, POM, XRD, rheological measurements and enzymatic degradation. The results show that copolymerization based on the DA reaction effectively avoids the phase separation of PPDO and PLA. Among the products, DA4700 showed a better crystallization performance than PLA, and the half-crystallization time was 2.8 min. Compared to PPDO, the heat resistance of the DA copolymers was improved and the Tm increased from 93 °C to 103 °C. Significantly, the rheological data also confirmed that the copolymer was self-healing and showed obvious self-repairing properties after simple tempering. In addition, an enzyme degradation experiment showed that the DA copolymer can be degraded by a certain amount, with the degradation rate lying between those of PPDO and PLA.

On-Demand PROTAC Scavenging Using Click Chemistry

Key words PROTACs - ligation - click chemistry - targeted protein degradation - inverse-electron-demand Diels–Alder reaction

Demystifying Solvent Effects on Diels–Alder Reactions in Pure and Mixed Solvents: A Combined Electronic DFT and QM/MM Study

Although solvent effects on chemical reactions in pure solvents are well elucidated, both reaction mechanisms and solvent effects in mixed solvents remain poorly understood. Herein, the free energy profiles and the solute–solvent energy pair distribution of the Diels–Alder reaction in pure water, acetonitrile (ACN), carbon tetrachloride (CTC), and their mixtures ACN-water and ACN-CTC are calculated using the quantum and molecular mechanical (QM/MM) Monte Carlo method. The results show that the presence of solvent can significantly reduce the reaction free energy barrier, and the barrier in the mixed solvent is intermediate between the two pure solvents. Additionally, the free energy decomposition analysis demonstrated that the QM region dominates the reaction free energy. Electronic DFT calculations are employed to delineate the interactions between reactants and solvent molecules in pure and mixed solvents, with a particular focus on the role of electrostatic potential characteristics and an independent gradient model based on Hirshfeld partition. By rigorously analyzing these interactions, this study demystifies the mechanism underlying the phenomenon of preferential solvation and competition for reacting sites in mixed solvents, which alters the microenvironment of the solute.

Synthesis and Properties of Dynamic Crosslinking Polyurethane/PEG Shape-Stable Phase Change Materials Based on the Diels–Alder Reaction

Phase change materials (PCMs) can absorb and release energy while keeping the temperature constant; hence, they play a crucial role in the thermal management field. Shape-stable phase change materials (SSPCMs) were synthesized by chemical crosslinking to address the liquid leakage problem of solid–liquid phase change materials (SLPCMs) during the phase change process. However, the abandoned SSPCMs cannot be reused and recycled, which seriously restricts their practical application. Herein, a polyurethane network containing Diels–Alder bonds was used as the enclosure compound to obtain the encapsulation of polyethylene glycol (PEG), and then, the chemical structure, crystallization behavior, and phase transition ability of SSPCMs were systematically investigated. The results showed that the SSPCMs-3 sample (300 wt % PEG) had the best comprehensive performance, an enthalpy value of 171.7 J/g, and no leakage at 80 °C for 1 h. Moreover, the structure, crystallization behavior, and phase transition ability of SSPCMs could also basically remain unchanged after multiple thermal cycling and reprocessing.

I2-Promoted gem-Diarylethene Involved Aza-Diels–Alder Reaction and Wagner–Meerwein Rearrangement: Construction of 2,3,4-Trisubstituted Pyrimido[1,2-b]indazole Skeletons

A [3 + 1 + 2] cyclization-rearrangement reaction scheme was developed to synthesize pyrimido[1,2-b]indazoles from aryl methyl ketones, 3-aminoindazoles, and gem-diarylethenes. This metal-free process proceeds via a sequential aza-Diels-Alder reaction and Wagner-Meerwein rearrangement, and a possible reaction mechanism was demonstrated based on control experiments. This method exhibits good substrate compatibility and allows simple reaction conditions. Moreover, the products display significant aggregation-induced emission characteristics after simple modifications.

Self‐Accelerating Diels–Alder Reaction for Preparing Polymers of Intrinsic Microporosity

AbstractIt is a formidable challenge in polycondensation to simultaneously construct multiple covalent bonds to prepare double‐stranded polymers of intrinsic microporosity (PIMs) with fused multicyclic linkages. To the best of our knowledge, this is the first study to develop a self‐accelerating Diels–Alder reaction for successfully preparing double‐stranded PIMs with fused multicyclic backbone structures. A self‐accelerating Diels–Alder reaction was developed based on the [4+2] cycloaddition of sym‐dibenzo‐1,5‐cyclooctadiene‐3,7‐diyne (DIBOD) and ortho‐quinone compounds. In this reaction, the cycloaddition of ortho‐quinone with the first alkyne of DIBOD activates the second alkyne, which reacts with ortho‐quinone at a rate constant 192 times larger than that of the original alkyne. Using this self‐accelerating reaction to polymerize DIBOD and spirocyclic/cyclic difunctional ortho‐quinone monomers, a novel stoichiometric imbalance‐promoted step‐growth polymerization method was developed to prepare PIMs. The resultant PIMs possess intrinsic ultramicropores with pore sizes between 0.45 to 0.7 nm, high specific surface areas above 646 m2 g−1, and good H2 separation performance.

Scalable synthesis of highly exfoliated, water-dispersible boron nitride nanosheets for nano-fibrillated cellulose membrane toughening

A very simple solid-state Diels Alder reaction of bulk boron nitride (BN) with maleic anhydride followed by ultrasonication in an aqueous solution was used to mass production of maleic acid functionalized highly exfoliated water dispersible single and few layers of boron nitride nanosheets (BNNS-MA). We demonstrate that as-synthesized BNNS-MA can be used to reinforce and toughen nano-fibrillated cellulose membranes.

Simple Access to Isoxazole-Containing Heterocyclic Hybrids: Isoxazole/Oxazole and Isoxazole/Pyridine

The synthesis of substituted isoxazole–oxazole hybrids by the noncatalytic reaction of methyl 2-diazo-2-(alkyl/aryl/hetarylisoxazol-5-yl)acetates with alkyl and aryl cyanides has been reported. According to DFT calculations, the reaction proceeds through the intermediate formation of a nitrile ylide and its subsequent cyclization at the carbonyl oxygen. The reaction of acrylonitrile with methyl 2-diazo-2-(isoxazol-5-yl)acetate proceeds quite differently and leads to a mixture of the cis and trans isomers of cyclopropanes, which, according to DFT calculations, are formed by the cycloaddition of a diazo-derived carbene to the C=C bond of acrylonitrile. The hetero-Diels–Alder reaction of the 5-alkoxyoxazole moiety of isoxazole–oxazole hybrids makes it possible to obtain isoxazole–pyridine hybrids, albeit in low yield.

The Diels–Alder reaction in the synthesis of fused heterocyclic aromatic compounds

The Diels–Alder reaction in the synthesis of fused heterocyclic aromatic compounds

Method for the synthesis of chromenopyrimidine-fused azoles by copper-catalyzed intramolecular hetero-Diels–Alder reaction

Method for the synthesis of chromenopyrimidine-fused azoles by copper-catalyzed intramolecular hetero-Diels–Alder reaction

Reactivity of Olefin Functionalities of Dicyclopentadiene in the Diels–Alder Reaction with Thionylaniline

Reactivity of Olefin Functionalities of Dicyclopentadiene in the Diels–Alder Reaction with Thionylaniline

Transition-Metal-Free Dehydrogenation of Benzyl Alcohol for C-C and C-N Bond Formation for the Synthesis of Pyrazolo[3,4-b]pyridine and Pyrazoline Derivatives.

A series of cascade reactions that produce a range of functionalized aromatic heterocyclic compounds with pyrazole/pyrazoline cores have been developed. The method relies on a metal-free dehydrogenative process to produce in-situ benzaldehydes. The produced benzaldehyde was then allowed to react with some other substances, including acetophenone, pyrazole amine, and phenylhydrazine. The intermediate produced from these substrates underwent several chemical processes, including electrocyclization, the aza-Diels-Alder reaction, and the formation of intramolecular C-N bonds. These positive outcomes would open up the possibility of producing biologically active pyrazolo[3,4-b]pyridine and pyrazoline derivatives through a variety of possible reactions.

2-Butyne Biscarbonate as a "Bridge" in Rhodium(III)-Catalyzed [4 + 2] Cyclization and Diels-Alder Reaction.

Described herein is the development of an unprecedented approach to construct multiple heterocycles with high selectivity through Rh(III)-catalyzed two- or three-component cyclization reaction from simple and readily available starting materials: N-methoxybenzamides, 2-butyne biscarbonate, and maleimides. This methodology provides an efficient strategy for the synthesis of diverse and complicated heterocycles in a one-pot manner and displays excellent features of extremely mild reaction conditions, easy operation, excellent regioselectivity, and good functional group compatibility.

Cover Feature: Substituent Effects in Bioorthogonal Diels–Alder Reactions of 1,2,4,5‐Tetrazines (Chem. Eur. J. 29/2023)

The fundamental mechanism driving the high reactivity of mono-substituted tetrazines is explored through substituent effects in the bioorthogonal Diels–Alder reactions of 1,2,4,5-tetrazines. Through computational analysis, the study unveils how an asynchronous approach of the reaction partner can mitigate adverse interactions during the reaction, leading to a reduction in the reaction barrier height. More information can be found in the Research Article by D. Svatunek and co-workers (DOI: 10.1002/chem.202300345).

Synthesis of Diastereomeric 8‐Fluoro‐ABC‐Steroid Building Blocks

AbstractAn eight‐step linear sequence for the preparation of two diastereomers of an 8‐fluoro‐ABC‐steroid building block was developed. Key step was an intramolecular Diels–Alder reaction of an intermediate o‐quinodimethane formed from a benzocyclobutene substituted with a 5‐fluorohex‐5‐en‐4‐one chain. This side chain was prepared from 6‐chlorohex‐1‐ene by bromofluorination, elimination of HBr, Finkelstein reaction and alkylation of a literature‐known benzocyclobutene derivative with the thus‐formed 6‐iodo‐2‐fluorohex‐1‐ene. Allylic oxidation of side chain's fluorovinyl moiety to an α‐fluoro‐α,β‐unsaturated ketone completed the preparation of the precursor for the [4+2]‐cycloaddition.

Anharmonic Correction to Free Energy Barriers from DFT-Based Molecular Dynamics Using Constrained Thermodynamic Integration.

For the calculation of anharmonic contributions to free energy barriers, constrained thermodynamic λ-path integration (λ-TI) from a harmonic reference force field to density functional theory is presented as an alternative to the established Blue Moon ensemble method (ξ-TI), in which free energy gradients along the reaction coordinate ξ are integrated. With good agreement in all cases, the λ-TI method is benchmarked against the ξ-TI method for several reactions, including the internal CH3 group rotation in ethane, a nucleophilic substitution of CH3Cl, a retro-Diels-Alder reaction, and a proton transfer in zeolite H-SSZ-13. An advantage of λ-TI is that one can use virtually any reference state to compute anharmonic contributions to reaction free energies or free energy barriers. This is particularly relevant for catalysis, where it is now possible to compute anharmonic corrections to the free energy of a transition state relative to any reference, for example, the most stable state of the active site and the reactants in the gas phase. This is in contrast to ξ-TI, where free energy barriers can only be computed relative to an initial state with all reactants coadsorbed. Finally, the Bennett acceptance ratio method combined with λ-TI is demonstrated to reduce the number of required integration grid points with tolerable accuracy, favoring thus λ-TI over ξ-TI in terms of computational efficiency.

Highly Thermally Stable, Reversible, and Flexible Main Chain Type Benzoxazine Hybrid Incorporating Both Polydimethylsiloxane and Double-Decker Shaped Polyhedral Silsesquioxane Units through Diels-Alder Reaction.

This work synthesizes a new bifunctional furan derivative (PDMS-FBZ) through a sequence of hydrosilylation of nadic anhydride (ND) with polydimethylsiloxane (PDMS), reaction of the product with p-aminophenol to form PDMS-ND-OH, and its subsequent Mannich reaction with furfurylamine and CH2 O. Then, the main chain-type copolymer PDMS-DABZ-DDSQ is prepared through a Diels-Alder (DA) cycloaddition of PDMS-FBZ with the bismaleimide-functionalized double-decker silsesquioxane derivative DDSQ-BMI. Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy confirm the structure of this PDMS-DABZ-DDSQ copolymer; differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic mechanical analysis (DMA) reveal it to have high flexibility and high thermal stability (Tg = 177 °C; Td10 = 441 °C; char yield = 60.1 wt%); contact angle measurements reveal a low surface free energy (18.18 mJ m-2 ) after thermal ring-opening polymerization, because the inorganic PDMS and DDSQ units are dispersed well, as revealed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). This PDMS-DABZ-DDSQ copolymer possesses reversible properties arising from the DA and retro-DA reactions, suggesting its possible application as a functional high-performance material.

Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application.

In this study, diselenide (Se-Se) and disulfide (S-S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)2k-b-poly(furfuryl methacrylate)1.5k (PEO2k-b-PFMA1.5k), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO2k-b-PFMA1.5k from FMA monomers and PEO2k-Br initiators. An anti-cancer drug, doxorubicin (DOX), was incorporated into PFMA hydrophobic parts of the polymeric micelles, which were then cross-linked with maleimide cross-linkers, 1,6-bis(maleimide) hexane, dithiobis(maleimido) ethane and diselenobis(maleimido) ethane via Diels-Alder reaction. Under physiological conditions, the structural stability of both S-S and Se-Se CCL micelles was maintained; however, treatments with 10 mM GSH induced redox-responsive de-cross-linking of S-S and Se-Se bonds. In contrast, the S-S bond was intact in the presence of 100 mM H2O2, while the Se-Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO2k-b-PFMA1.5k-Se)2 micelles varied more significantly in response to changes in the redox environment than (PEO2k-b-PFMA1.5k-S)2 micelles. In vitro release studies showed that the developed micelles had a lower drug release rate at pH 7.4, whereas a higher release was observed at pH 5.0 (tumor environment). The micelles were non-toxic against HEK-293 normal cells, which revealed that they could be safe for use. Nevertheless, DOX-loaded S-S/Se-Se CCL micelles exhibited potent cytotoxicity against BT-20 cancer cells. Based on these results, the (PEO2k-b-PFMA1.5k-Se)2 micelles can be more sensitive drug carriers than (PEO2k-b-PFMA1.5k-S)2 micelles.

First Diels–Alder reaction of a N-nitrogen-substituted iminium ion as dienophile furnishing N-amino-substituted 1,2,5,6-tetrahydropyridines

The exploratory and preliminary work on the reaction of 1-(methoxydiphenylmethyl)-2-methyldiazene with 1,3-dienes reveals a remarkable dichotomy furnishing different heterocyclic Diels–Alder products depending on the presence or absence of water. In contrast to the acid-induced hydrolysis of the N,O-ketal starting material with 1,3-dienes furnishing 1-methyl-1,2,3,6-tetrahydropyridazines (preceding communication), the same acid-promoted reaction albeit under exclusion of water affords N-(methyleneamino)-1,2,5,6-tetrahydropyridines. The serendipitous discovery of the novel 1,2,5,6-tetrahydropyridines was corroborated by an alternative and independent synthesis providing the in situ generated formaldehyde benzophenone azine and its conjugate acid, 2-(diphenylmethylene)-1-methylenehydrazin-1-ium ion. The protonated azine serving as the putative dienophile resembles the first example of an N-nitrogen-substituted iminium ion employed as a dienophile in a bona fide normal electron-demand Diels–Alder reaction.Graphical abstract