Diels-Alder Cycloaddition Research Articles

Fullerene-hybridized Fused-ring Electron Acceptor with High Dielectric Constant and Isotropic Charge Transport for Organic Solar Cells.

A novel isotropic fullerene-hybridized fused-ring electron acceptor, designated C60-Y, has been synthesized via a mild [4+2] Diels-Alder cycloaddition reaction with fullerene C60 to enhance the performance of organic solar cells (OSCs). Comparative analysis shows that C60-Y significantly outperforms the control acceptor Me-Y, with a notable increase in the relative dielectric constant from 2.79 to 3.95. This improvement enhances exciton dissociation and reduces non-radiative energy losses. Additionally, the isotropic molecular packing of C60-Y, similar to fullerene, facilitates efficient interface formation with donor polymers and improves charge mobility. As a result, incorporating C60-Y as an electron acceptor increases the power conversion efficiency (PCE) of binary OSCs to 15.02%, surpassing the 13.31% achieved with Me-Y. Moreover, when integrated into a ternary blend system, an impressive PCE of 19.22% is achieved, top-performing among reported ternary OSCs utilizing fullerene derivatives as the third component. These results suggest that fullerene-hybridized acceptors like C60-Y hold great potential for advancing high-efficiency OSCs by enhancing exciton dissociation, reducing energy losses, and improving charge mobility.

Stereochemical Shape Morphing in Diels-Alder Polymer Networks.

The intrinsic reversibility of dynamic covalent bonding, such as the furan-maleimide Diels-Alder (DA) cycloaddition reactions, enables reprocessable, self-healing polymer materials that can be reconfigured via the mechanism of solid-state plasticity. In this work, the temperature-dependent exchange rates of stereochemically distinct endo and exo DA bonds are leveraged to achieve tunable, temperature- and stress-activated shape morphing in Diels-Alder polymer (DAP) networks. Through thermal annealing, ≈35% of endo DA isomers are converted in neat DAP networks to the thermodynamically favored exo form, achieving ≈97% exo after complete annealing at 60°C. This conversion results in a ≈1.7 fold increase in elastic modulus, from 1.7 to 3.0MPa, and significantly alters the stress relaxation and shape recovery behavior. Spatially resolved annealing, is further showcased enabling the precise control of spatial distributions of endo and exo DA bonds across planar geometries. The locally distinct concentrations of endo/exo isomers, achieved by temperature-induced conversion of endo DA isomers to the thermodynamically stable exo DA isomers, gave rise to the spatial distributions of stress relaxation rates and elastic strain recovery mismatch to enable controlled stereochemical shape morphing. This approach provides a simplified, thermally driven method for shape morphing, with potential applications in soft robotics and flexible electronics.

Advancements in Inverse-Electron-Demand Diels–Alder Cycloaddition of 2-Pyrones: Mechanisms, Methodologies

The Diels-Alder (DA) cycloaddition is well-known for its effectiveness in synthesizing natural products and multifunctional materials. This article specifically explores the inverse-electron-demand Diels-Alder (IEDDA) cycloaddition involving 2-pyrones, which display ambiphilic properties due to their unique electronic characteristics. We investigate the mechanisms underlying IEDDA, with a focus on how electron-donating and electron-withdrawing substituents influence reactivity and product selectivity. Various methodologies are reviewed, encompassing non-catalytic and catalytic approaches. Special attention is given to advancements in microwave-assisted techniques and high-pressure conditions, which enhance both reaction efficiency and selectivity. Additionally, the synthesis of chiral bridged bicyclic lactones from substituted 2-pyrones is examined, illustrating their versatility in organic synthesis. This review underscores the significance of IEDDA cycloaddition in pioneering new synthetic routes for building complex molecular structures.

Applications of Diels-Alder Chemistry in Biomaterials and Drug Delivery.

Recent studies, leveraging click chemistry reactions, have significantly advanced the fields of biomaterials and drug delivery. Of these click reactions, the Diels-Alder cycloaddition is exceptionally valuable for synthetic organic chemistry and biomaterial design, as it occurs under mild reaction conditions and can undergo a retrograde reaction, under physiologically relevant conditions, to yield the initial reactants. In this review, potential applications of the Diels-Alder reaction are explored within the nexus of biomaterials and drug delivery. This includes an emphasis on key platforms such as polymers, nanoparticles, and hydrogels which utilize Diels-Alder for drug delivery, functionalized surfaces, bioconjugation, and other diverse applications. Specifically, this review will focus on the use of Diels-Alder biomaterials in applications of tissue engineering and cancer therapies, while providing a discussion of the advantages, platforms, and applications of Diels-Alder click chemistry.

A Syndiotactic Polymer via Spontaneous Exoselective Single-Crystal-To-Single-Crystal Topochemical Diels-Alder Cycloaddition Reaction.

We designed and synthesized an amide-based monomer decorated with furan as the diene unit and maleimide as the dienophile unit at its termini. Single-crystal X-ray diffraction (SCXRD) analysis of its crystal revealed a head-to-tail arrangement of molecules with furan and maleimide groups of neighboring molecules proximally placed in an arrangement suitable for their topochemical Diels-Alder cycloaddition (TDAC) to form a linear polymer. The monomer underwent a spontaneous single-crystal-to-single-crystal (SCSC) polymerization at room temperature, yielding a linear polymer with oxa-bicyclic linkage. SCXRD analysis revealed that the cycloaddition occurred in an exoselective manner, and the absolute stereochemistry of the oxa-bicyclic linkage alternated in successive repeat units, leading to a syndiotactic linear polymer. The polymerization can be accelerated by heating the powder at 120 °C; the topochemical nature of the high-temperature reaction was established by time dependent differential scanning calorimetry (DSC), time-dependent powder X-ray diffraction (PXRD), and UV-visible spectroscopic analysis; the polymer was characterized using solid-state NMR spectroscopy and MALDI-TOF mass spectrometry.

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

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

Perylene-Embedded Helical Nanographenes with Emission up to 1010 nm: Synthesis, Structures, and Chiroptical Properties.

Near-infrared (NIR) circularly polarized absorbing or emitting materials offer distinct advantages over their visible-light counterparts and have attracted considerable interest across various fields. Materials exhibiting NIR chiroptical properties with high fluorescence quantum yields (ΦF) are particularly rare. In this study, we report the synthesis of a series of helical nanographenes (1, 2, 3, and 4), where perylene is fused with one to four hexa-peri-hexabenzocoronene (sub)units via a strategy involving Diels-Alder cycloaddition followed by Scholl reaction. X-ray crystallographic analysis confirmed their structures, revealing helicene moieties integrated into a highly contorted framework. Benefiting from a similar distribution pattern of frontier molecular orbitals to perylene and extended π-conjugation, compounds 1-4 demonstrate respectable ΦF values of 31.9%, 15.0%, 13.7%, and 6.5%, respectively, with emission maxima reaching up to 1010 nm. Their enantiopure forms, isolated by preparative chiral HPLC, exhibit distinct circular dichroism signals and circularly polarized luminescence across a broad spectral range, extending from the ultraviolet to the NIR.

Multicomponent synthesis of 7-(diethylamino)coumarin–pyrrolo[3,4-b]pyridin-5-one conjugates and modulation of their twisted intramolecular charge transfer (TICT) processes

By coupling an Ugi-Zhu three-component reaction to a cascade sequence (aza Diels-Alder cycloaddition / N-acylation / decarboxylation / dehydration) into a one-pot process, seven new 7-(diethylamino)coumarin-pyrrolo[3,4-b]pyridin-5-one bis-heterocyclic conjugates were synthesized in moderate overall yields (15–38%). Next, the photophysical properties of all products were determined using UV-Vis and fluorescence spectroscopy. These products exhibited fluorescence quantum yields (FQY) ranging from 17% to 25%. In contrast, one of their precursors, the free 7-(diethylamino)-3-carbaldehyde displayed a low FQY of 2%, and, also exhibited dual emission across all solvents used for the measurements. The increase in quantum yield observed upon incorporation of the coumarin moiety into MCR products was attributed to the inhibition of the twisted intramolecular charge transfer (TICT) process. This one naturally occurs in the free coumarin but was suppressed in the products due to a decrease in the acceptor strength of the substituent at position 3 of the coumarin moiety. Furthermore, the electronic structure of the compounds was computed by DFT/TD-DFT calculations allowing to determine which molecular orbitals (MO) were involved in the electronic transitions.

Probing the alkylidene carbene-strained alkyne equilibrium in polycyclic systems via the Fritsch-Buttenberg-Wiechell rearrangement.

Strained cycloalkynes are valuable building blocks in synthetic chemistry due to their high degree of reactivity and ability to form structurally complex scaffolds, common features of many pharmaceuticals and natural products. Alkylidene carbenes provide a pathway to the formation of strained cycloalkynes through Fritsch-Buttenberg-Wiechell rearrangements, but this strategy, like other methods of alkyne generation, is believed to depend upon a thermodynamic equilibrium that favors the alkyne over the carbene. Herein three highly strained, polycyclic alkynes, previously thought to be thermodynamically inaccessible, are generated under mild conditions and intercepted through Diels-Alder cycloaddition with a diene trapping agent. The use of a different trapping agent also allows for the interception of the alkylidene carbene, providing the first instance in which both an exocyclic alkylidene carbene and its cycloalkyne Fritsch-Buttenberg-Wiechell rearrangement product have been trapped.

Diels–Alder Cycloaddition of Cyclopentadiene with α-Olefins for the Synthesis of High-Performance Sustainable Aviation Fuels

Diels–Alder Cycloaddition of Cyclopentadiene with α-Olefins for the Synthesis of High-Performance Sustainable Aviation Fuels

Recycling of Rare Earth Elements: From E-Waste to Stereoselective Catalytic Reactions.

Raw mixtures of Rare Earths Elements, REE, recovered by E-waste, were used as catalysts to promote the (stereoselective) synthesis of highly valuable compounds. Y2O3, the major species that is recovered by the E-waste, can be easily converted into the catalytically active Y(OTf)3 that is able to efficiently promote the Michael addition of indoles to benzylidene malonates and the stereoselective Diels-Alder cycloaddition between cyclopentadiene and 4-(S)-3 acryloyl 4-tert-butyl 2-oxazolidinone. Additionally, the raw mixtures were immobilized onto silica and used to construct packed reactors, resulting in values for Productivity and Space-Time Yields that were significantly higher than those of the corresponding batch conversions. Notably, the prepared cartridge employed in the model Michael reaction maintained its catalytic efficiency for more than 4 days of continuous running.

Biomimetic and Concise Total Syntheses of Prenylated and Bicyclo[2.2.2]diazaoctane-Containing Indole Alkaloids Including Taichunamide A, Notoamide N and Versicolamide B.

Total syntheses of the title prenylated indole alkaloids together with seven others are reported. Biogenetic considerations have been employed in devising the reaction sequences leading to these targets with, in the opening stages, electrochemically-derived indole-3-carboxaldehyde 15 being subject to an aldol-type condensation reaction involving diketopiperazine derivative 19. This led, after prototopic shifts, intramolecular Diels-Alder cycloaddition and hydrolysis/deprotection steps, to the racemic forms of the bicyclo[2.2.2]diazaoctane-containing natural product stephacidin A (2) and its C6 epimer 3. Epoxidation of the last compound afforded, following rearrangement of the primary oxidation products, a mixture of (±)-taichunamide A [(±)-4] and (±)-versicolamide B [(±)-7]. Related protocols allowed for the conversion of (±)-stephacidin A [(±)-2] into (±)-notoamide B [(±)-5]. Analogous aldol condensation, nucleophilic reduction, and epoxidation steps led to the formation of (-)-notoamide E and its conversion into notoamide C as well as the indole fragmentation product amoenamide E. A late-stage chlorination reaction applied to (±)-stephacidin A provided access to the spirocyclic oxindole (±)-notoamide N [(±)-6].

Cycloadditions of 4-Alkenyl-2-aminothiazoles with Nitroalkenes in the Formal Synthesis of Pramipexole: An Experimental and Computational Study.

4-Alkenyl-2-dialkylaminothiazoles act as in-out dienes in [4 + 2] cycloaddition reactions with nitroalkenes, furnishing 2-amino-6-nitro-4,5,6,7-tetrahydrobenzothiazoles in moderate to good yields, accompanied by a subsequent 1,3-H migration. These transformations proceed with exquisite site-, regio-, and diastereoselectivity. This strategy is further enriched by revealing a novel route for pramipexole synthesis. The examination of the potential energy surfaces associated with the four possible reaction pathways for the Diels-Alder cycloaddition (relative approach of the diene-dienophile and endo/exo approach of the nitro group) not only aligns with experimental observations but also unveils key mechanistic insights. Specifically, computational analyses uncover the favored pathway yielding 6-nitro-4,5,6,7-tetrahydrobenzothiazoles, with some instances proceeding through a two-step mechanism involving a tandem sequence of chemical processes, and the influence of various factors such as dienophile structure and the approach mode of the nitro group. Additionally, the stabilization of the exo-transition states, particularly facilitated by phenyl substitution in the dienophile, is highlighted. Asynchronicity, dipole moment, and other parameters indicative of polar character further characterize these Diels-Alder reactions. Conceptual DFT calculations underscore the pivotal role of the 1,3-thiazole ring in enhancing dienic activation and dictating regioselectivity, emphasizing interactions between the C5 of the thiazole nucleus and the Cβ atom of the nitroalkenes.

Large Molecular Rotation in Crystal Changes the Course of a Topochemical Diels–Alder Reaction from a Predicted Polymerization to an Unexpected Intramolecular Cyclization

AbstractA designed anthracene‐based monomer for topochemical Diels–Alder cycloaddition polymerization crystallized with head‐to‐tail arrangement of molecules, as revealed by single‐crystal X‐ray diffraction (SCXRD) analysis. The diene and dienophile units of adjacent monomer molecules are aligned at an average distance of 4.6 Å, suggesting a favorable crystalline arrangement for their intermolecular Diels–Alder cycloaddition reaction to form a linear polymer. Surprisingly, heating the monomer crystals at a temperature above 125 °C resulted in the formation of intramolecular Diels–Alder cycloadduct, which could be characterized by various spectroscopy and SCXRD analysis. Various time‐dependent studies such as NMR, PXRD, and DSC, studies established that the reaction followed topochemical pathway. Schmidt's topochemical postulates are generally used to predict the topochemical reactivity and product, by analyzing the crystal structure of the reactant. Though the crystal arrangement predicted polymerization, upon heating, the molecule avoided this pathway by undergoing a large rotation to form an intramolecular cycloadduct. Theoretical calculations supported the feasibility of the rotation, exploiting the flexibility of the molecule and voids present. These findings caution that the reliance on Schmidt's criteria for topochemical reactions may sometimes be misleading, especially in heat‐induced reactions.

Large Molecular Rotation in Crystal Changes the Course of a Topochemical Diels-Alder Reaction from a Predicted Polymerization to an Unexpected Intramolecular Cyclization.

A designed anthracene-based monomer for topochemical Diels-Alder cycloaddition polymerization crystallized with head-to-tail arrangement of molecules, as revealed by single-crystal X-ray diffraction (SCXRD) analysis. The diene and dienophile units of adjacent monomer molecules are aligned at an average distance of 4.6 Å, suggesting a favorable crystalline arrangement for their intermolecular Diels-Alder cycloaddition reaction to form a linear polymer. Surprisingly, heating the monomer crystals at a temperature above 125 °C resulted in the formation of intramolecular Diels-Alder cycloadduct, which could be characterized by various spectroscopy and SCXRD analysis. Various time-dependent studies such as NMR, PXRD, and DSC, studies established that the reaction followed topochemical pathway. Schmidt's topochemical postulates are generally used to predict the topochemical reactivity and product, by analyzing the crystal structure of the reactant. Though the crystal arrangement predicted polymerization, upon heating, the molecule avoided this pathway by undergoing a large rotation to form an intramolecular cycloadduct. Theoretical calculations supported the feasibility of the rotation, exploiting the flexibility of the molecule and voids present. These findings caution that the reliance on Schmidt's criteria for topochemical reactions may sometimes be misleading, especially in heat-induced reactions.

Platinum‐Catalyzed Isomerization of Cyclopropenes to 1,3‐Dienes

AbstractHerein we report a platinum‐catalyzed isomerization of cyclopropenes to 1,3‐dienes. Diverse dienylated alcohols were obtained in 42–98 % yield. The synthetic potential of the products was demonstrated by their use in Diels–Alder cycloadditions with various dienophiles. Isotope labelling studies provide strong support for a mechanism involving pericyclic [1,5]‐σ‐bond rearrangement of a vinyl platinum carbene intermediate.

Diels-Alder Cycloaddition of 2,5-Bis(hydroxymethyl)furan (BHMF) and N-Phenylmaleimide Derivatives.

Currently, amidst atmospheric menace where natural calamities such as wildfire and floods are becoming more frequent than ever, biobased derivatives offer a sustainable alternative to conventional ways, for instance, petrochemical commodities. Biobased products, obtained from agricultural waste, including 5-(hydroxymethyl)furfural (HMF), 2,5-bis(hydroxymethyl)furan (BHMF), and 2,5-furandicarboxylic acid (FDCA) are promising chemical platforms in the biorefinery, which is yet to be explored. The Diels-Alder cycloaddition of BHMF and N-phenylmaleimide derivatives under optimal reaction conditions is investigated in this report. First, HMF is reduced to BHMF in the presence of NaBH4, and then the Diels-Alder reaction of BHMF and N-phenylmaleimide derivatives is investigated to produce Diels-Alder adducts. All novel compounds are synthesized in acceptable yields and effectively characterized by employing important techniques such as one-dimensional (1D) NMR spectroscopy (1H, 13C, DEPT-90, and DEPT- 135), two-dimensional (2D) NMR spectroscopy (1H-1H COSY, 1H-13C HSQC, and 1H-13C HMBC), IR spectroscopy, elemental analysis, mass spectrum (QTOF), and single-crystal X-ray diffraction (SC-XRD). Furthermore, this study underlines the necessity of sustainable synthetic methodologies and gives critical insights into the progress of ecologically friendly methodologies, providing a new avenue as a tunable precursor for the challenging functionalized polymer in the future.

The orientation dependence of cavity-modified chemistry.

Recent theoretical studies have explored how ultra-strong light-matter coupling can be used as a handle to control chemical transformations. Ab initio cavity quantum electrodynamics calculations demonstrate that large changes to reaction energies or barrier heights can be realized by coupling electronic degrees of freedom to vacuum fluctuations associated with an optical cavity mode, provided that large enough coupling strengths can be achieved. In many cases, the cavity effects display a pronounced orientational dependence. Here, we highlight the critical role that geometry relaxation can play in such studies. As an example, we consider a recent work [Pavošević et al., Nat. Commun. 14, 2766 (2023)] that explored the influence of an optical cavity on Diels-Alder cycloaddition reactions and reported large changes to reaction enthalpies and barrier heights, as well as the observation that changes in orientation can inhibit the reaction or select for one reaction product or another. Those calculations used fixed molecular geometries optimized in the absence of the cavity and fixed relative orientations of the molecules and the cavity mode polarization axis. Here, we show that when given a chance to relax in the presence of the cavity, the molecular species reorient in a way that eliminates the orientational dependence. Moreover, in this case, we find that qualitatively different conclusions regarding the impact of the cavity on the thermodynamics of the reaction can be drawn from calculations that consider relaxed vs unrelaxed molecular structures.

(Invited) Reactivity on Endohedral Metallofullerenes

Endohedral metallofullerenes (EMFs) are fullerene molecules with unique host-guest structures that allow chemists to manipulate encapsulated metal ions with the arsenal of organic chemistry, for potential applications including spin-quantum computing, single-molecule magnets, dynamic nuclear polarization, artificial photosynthesis, magnetic resonance imaging contrast agents, and therapeutic agents. To unleash the power to do so, the development of new reactions for EMFs has been an ongoing task.A key step to improve the solubility of EMFs as well as to obtain new materials for multiple applications is via exohedral functionalization. In medicine, for instance, water-soluble gadofullerenols are used as powerful contrast agents.1 Besides, the external groups might impart complementary features to EMFs that tune their physical properties for use as acceptors in polymer solar cells or as donor-acceptor dyad conjugates.2 Among the most used methods to obtain EMF monoadducts are cycloaddition reactions and radical additions, including the Diels-Alder cycloaddition, Bingel-Hirsch cyclopropanation, Prato 1,3-dipolar addition, carbene addition, etc. In these reactions, fullerenes typically play a similar electron-accepting role, thus their reactivity and regioselectivity are highly consistent. However, the reactivity of EMFs is far more complicated than of empty fullerenes due to the relatively low molecular symmetry and the influence of the encapsulated species. To understand the role of metal-cage interactions on the reactivity of EMFs is desirable for tuning their chemical reactivity.Here, we report the functionalization of actinide endofullerenes, in particular, the mono-EMFs U@C s(4)-C82 and U@C 2v(9)-C82, which their chemical reactivities were investigated through the Bingel-Hirsch (nucleophilic addition) and carbene addition (electrophilic addition) reactions. Interestingly, only for U@C 2v(9)-C82, the Bingel-Hirsch reaction leads to mono-adduct and multi-adduct compounds. Another subgroup of EMF that we study its reactivity here is the nitride clusterfullerenes, especially the Lu3N@Ih-C80, with high stability and high production yields, that results its chemical modification to be challenging. In this case, the reaction studied is the inverse-electron demand Diels-Alder (IEDDA) reaction and it will be compared to the corresponding reactivity on C60 fullerene. We show that Lu3N@Ih-C80presents higher reactivity than for C60, as well as, different features. 1Bolskar, R. D.; Benedetto, A. F.; Wilson, L. J.; Alford, J. M. et al. J. Am. Chem. Soc. 2003, 125, 5471-5478. 2Ross, R. B.; Cardona, C. M.; Guldi, D. M. et al. Nature Mater. 2009, 8, 208-212. Figure 1

Synthesis of 2‐Aminopyridine Derivatives via a Tandem CuAAC/Ring‐Cleavage/[4+2]‐Cycloaddition/Rearrangement Reaction Sequence

Abstract2H‐Azirines are an important class of small‐ring heterocycle that have been employed as versatile synthetic building blocks. Herein, a one‐pot CuAAC/ring‐cleavage/[4+2]‐cycloaddition/rearrangement reaction sequence involving terminal ynones, sulfonyl azides and 2H‐azirines is reported that leads to 2‐aminopyridine derivatives. In the first step, highly reactive N‐sulfonyl α‐acylketenimines are generated, via a CuAAC/ring‐cleavage process, from sulfonyl azides and terminal ynones and these undergo inverse electron‐demand Diels–Alder cycloaddition reactions with 2H‐azirines to form (isolable) 1,3‐oxazines that themselves undergo base‐promoted ring‐cleavage and rearrangement reactions to afford the title compounds.