Synthetic Challenge Research Articles

Rapid Access to 2,2-Disubstituted Indolines via Dearomative Indolic-Claisen Rearrangement: Concise, Enantioselective Total Synthesis of (+)-Hinckdentine A.

The construction of 2,2-disubstituted indolines has long presented a synthetic challenge without any general solutions. Herein, we report a robust protocol for the dearomative Meerwein-Eschenmoser-Claisen rearrangement of 3-indolyl alcohols that provides efficient access to 2-substituted and 2,2-disubstituted indolines. These versatile subunits are useful for natural product synthesis and medicinal chemistry. The title [3,3] sigmatropic rearrangement proceeds in generally excellent yield and transfers the C3-indolic alcohol chirality to the C2 position with high fidelity, thus providing a reliable method for the construction of enantioenriched 2,2-disubstituted indolines. The power of this methodology is demonstrated through the concise and strategically unique total synthesis of the marine natural product hinckdentine A, which features a dearomative Claisen rearrangement, a diastereocontrolled hydrogenation of the alkene product, a one-pot amide-to-oxime conversion using Vaska's complex, and a regioselective late-stage tribromination.

Ultrafine Homologous Ni2P–Co2P Heterostructures via Space‐Confined Topological Transformation for Superior Urea Electrolysis

AbstractConstructing effective electrocatalysts based on ultrafine heterostructures is a promising strategy for boosting catalytic performance by exposing active sites and increasing specific surface area. However, the fabrication of catalytically active heterostructures with elaborate architectures is still poorly developed owing to synthetic challenges, and the intrinsic mechanism of heterogeneous interfaces remains unclear because of insufficient evidence regarding real active sites. In this study, ultrafine homologous Ni2P–Co2P heterostructures (Ni2P–Co2P/C) are created using a topological transformation strategy from a Ni–Co layered double hydroxide/carbon (Ni–Co LDH/C) interconnected structure in a single nanosheet. When employed as catalysts in urea oxidation reaction (UOR), the Ni2P–Co2P/C heterostructures exhibit superior activity and stability, attributed to the optimized geometric and electronic structures of the catalytic sites. Specifically, it takes an ultralow potential of 1.27 V to reach a current density of 10 mA cm−2 with a small Tafel slope of 28.71 mV dec−1. The operando analyses and calculation results reveal that cobalt incorporation can reduce the generation potential of the surface reconstructive active species and optimize the absorption/desorption energy of the intermediates. Overall, this study proposes an efficient and cost‐effective UOR electrocatalyst and offers a new high‐performance homologous heterostructure design for widespread application.

Assembling a Heterobimetallic Actinide Metal‐Organic Framework by a Reaction‐Induced Preorganization Strategy

AbstractPeriodically arranging coordination‐distinct actinides into one crystalline architecture is intriguing but of great synthetic challenge. We report a rare example of a heterobimetallic actinide metal–organic framework (An‐MOF) by a unique reaction‐induced preorganization strategy. A thorium MOF (SCU‐16) with the largest unit cell among all Th‐MOFs was prepared as the precursor, then the uranyl was precisely embedded into the MOF precursor under oxidation condition. Single crystal of the resulting thorium‐uranium MOF (SCU‐16‐U) shows that a uranyl‐specific site was in situ induced by the formate‐to‐carbonate oxidation reaction. The heterobimetallic SCU‐16‐U exhibits multifunction catalysis properties derived from two distinct actinides. The strategy proposed here offers a new avenue to create mixed‐actinide functional material with unique architecture and versatile functionality.

Assembling a Heterobimetallic Actinide Metal-Organic Framework by a Reaction-Induced Preorganization Strategy.

Periodically arranging coordination-distinct actinides into one crystalline architecture is intriguing but of great synthetic challenge. We report a rare example of a heterobimetallic actinide metal-organic framework (An-MOF) by a unique reaction-induced preorganization strategy. A thorium MOF (SCU-16) with the largest unit cell among all Th-MOFs was prepared as the precursor, then the uranyl was precisely embedded into the MOF precursor under oxidation condition. Single crystal of the resulting thorium-uranium MOF (SCU-16-U) shows that a uranyl-specific site was in situ induced by the formate-to-carbonate oxidation reaction. The heterobimetallic SCU-16-U exhibits multifunction catalysis properties derived from two distinct actinides. The strategy proposed here offers a new avenue to create mixed-actinide functional material with unique architecture and versatile functionality.

Biodegradable Piezoelectric Polymers: Recent Advancements in Materials and Applications.

Recent materials, microfabrication, and biotechnology improvements have introduced numerous exciting bioelectronic devices based on piezoelectric materials. There is an intriguing evolution from conventional unrecyclable materials to biodegradable, green, and biocompatible functional materials. As a fundamental electromechanical coupling material in numerous applications, novel piezoelectric materials with a feature of degradability and desired electrical and mechanical properties are being developed for future wearable and implantable bioelectronics. These bioelectronics can be easily integrated with biological systems for applications, including sensing physiological signals, diagnosing medical problems, opening the blood-brain barrier, and stimulating healing or tissue growth. Therefore, the generation of piezoelectricity from natural and synthetic bioresorbable polymers has drawn great attention in the research field. Herein, the significant and recent advancements in biodegradable piezoelectric materials, including natural and synthetic polymers, their principles, advanced applications, and challenges for medical uses, are reviewed thoroughly. The degradation methods of these piezoelectric materials through in vitro and in vivo studies are also investigated. These improvements in biodegradable piezoelectric materials and microsystems could enable new applications in the biomedical field. In the end, potential research opportunities regarding the practical applications are pointed out that might be significant for new materials research.

Enantioenriched Boron C,N-Chelates via Chirality Transfer.

Molecules stereogenic only at tetrahedral boron atoms show great promise for applications, for example as chiroptical materials, but are scarcely investigated due to their synthetic challenge. Hence, this study reports a two-step synthesis of enantioenriched boron C,N-chelates. First, the diastereoselective complexation of alkyl/aryl borinates with chiral aminoalcohols furnished boron stereogenic heterocycles in up to 86 % yield and d.r. >98 : 2. Treatment of these O,N-complexes with chelate nucleophiles was surmised to transfer the stereoinformation via the ate-complex into the C,N-products. This chirality transfer succeeded by substitution of the O,N-chelates with lithiated phenyl pyridine to give boron stereogenic C,N-chelates in up to 84 % yield and e.r. up to 97 : 3. The chiral aminoalcohol ligands could be recovered after isolation of the C,N-chelates. The chirality transfer tolerated alkyl, alkynyl and (hetero-)aryl moieties at boron and could be further extended by post-modification: transformations such as catalytic hydrogenations or sequential deprotonation/electrophilic trapping were feasible while maintaining the stereochemical integrity of the C,N-chelates. Structural aspects of the boron chelates were studied by variable temperature NMR and X-ray diffraction.

Recent advances on the synthesis, structure, and properties of polyoxotantalates

Polyoxotantalates (POTas) are an important branch of polyoxometalates (POMs) that remain largely undeveloped compared with other members of the POM family including polyoxovanadates, polyoxotungstates, polyoxomolybdates, and polyoxoniobates. Owing to their promising applications in diverse fields such as photo/electrocatalysis, ion conduction, environmental protection, and magnetism, the development of synthetic strategies for new POTas has attracted continuous interest over the past decades. This review summarizes the current status in the development of POTas, including their synthetic methods, crystal structures, physicochemical properties, and potential applications. Additionally, synthetic challenges and prospects are also discussed. It is hoped that this review will be of reference value for the further development of POTas.

Synthetic Study toward Triterpenes from the Schisandraceae Family of Natural Products.

Triterpenoid natural products from the Schisandraceae family have long presented a significant synthetic challenge. Lancifodilactone I, a member of the family not previously synthesized, was identified as a key natural product target, from which many other members could be synthesized. We envisaged that the core ring system of lancifodilactone I could be accessed by a strategy involving palladium-catalysed cascade cyclisation of a bromoenynamide, via carbopalladation, Suzuki coupling and 8π-electrocyclisation, to synthesize the core 7,8-fused ring system. Exploration of this strategy on model systems resulted in efficient syntheses of 5,6- and 5,8-fused systems in high yields, which represent the first such cyclisation where the ynamide nitrogen atom is 'external' to the forming ring system. The enamide functionality resident in the cascade cyclisation product was found to be less nucleophilic than the accompanying tri-/tetrasubstituted alkene(s), enabling regioselective oxidations. Application of this strategy to 7,6-, and 7,8-fused systems, and ultimately the 'real' substrate, was ultimately thwarted by the difficulty of 7-membered ring closure, leading to side product formation. Nevertheless, a tandem bromoenynamide carbopalladation, Suzuki coupling and 6/8π-electrocyclisation was shown to be a highly efficient tactic for the formation of bicyclic enamides, which may find applications in other synthetic contexts.

Single-Crystal 2D Covalent Organic Frameworks for Plant Biotechnology.

Molecules chemically synthesized as periodic two-dimensional (2D) frameworks via covalent bonds can form some of the highest-surface area and -charge density particles possible. There is significant potential for applications such as nanocarriers in life sciences if biocompatibility can be achieved; however, significant synthetic challenges remain in avoiding kinetic traps from disordered linking during 2D polymerization of compatible monomers, resulting in isotropic polycrystals without a long-range order. Here, we establish thermodynamic control over dynamic control on the 2D polymerization process of biocompatible imine monomers by minimizing the surface energy of nuclei. As a result, polycrystal, mesocrystal, and single-crystal 2D covalent organic frameworks (COFs) are obtained. We achieve COF single crystals by exfoliation and minification methods, forming high-surface area nanoflakes that can be dispersed in aqueous medium with biocompatible cationic polymers. We find that these 2D COF nanoflakes with high surface area are excellent plant cell nanocarriers that can load bioactive cargos, such as the plant hormone abscisic acid (ABA) via electrostatic attraction, and deliver them into the cytoplasm of intact living plants, traversing through the cell wall and cell membrane due to their 2D geometry. This synthetic route to high-surface area COF nanoflakes has promise for life science applications including plant biotechnology.

Structure Elucidation of Secondary Metabolites: Current Frontiers and Lingering Pitfalls.

Analytical methods allow for the structure determination of submilligram quantities of complex secondary metabolites. This has been driven in large part by advances in NMR spectroscopic capabilities, including access to high-field magnets equipped with cryogenic probes. Experimental NMR spectroscopy may now be complemented by remarkably accurate carbon-13 NMR calculations using state-of-the-art DFT software packages. Additionally, microED analysis stands to have a profound effect on structure elucidation by providing X-ray-like images of microcrystalline samples of analytes. Nonetheless, lingering pitfalls in structure elucidation remain, particularly for isolates that are unstable or highly oxidized. In this Account, we discuss three projects from our laboratory that highlight nonoverlapping challenges to the field, with implications for chemical, synthetic, and mechanism of action studies. We first discuss the lomaiviticins, complex unsaturated polyketide natural products disclosed in 2001. The original structures were derived from NMR, HRMS, UV-vis, and IR analysis. Owing to the synthetic challenges presented by their structures and the absence of X-ray crystallographic data, the structure assignments remained untested for nearly two decades. In 2021, the Nelson group at Caltech carried out microED analysis of (-)-lomaiviticin C, leading to the startling discovery that the original structure assignment of the lomaiviticins was incorrect. Acquisition of higher-field (800 MHz 1H, cold probe) NMR data as well as DFT calculations provided insights into the basis for the original misassignment and lent further support to the new structure identified by microED. Reanalysis of the 2001 data set reveals that the two structure assignments are nearly indistinguishable, underscoring the limitations of NMR-based characterization. We then discuss the structure elucidation of colibactin, a complex, nonisolable microbiome metabolite implicated in colorectal cancer. The colibactin biosynthetic gene cluster was detected in 2006, but owing to colibactin's instability and low levels of production, it could not be isolated or characterized. We used a combination of chemical synthesis, mechanism of action studies, and biosynthetic analysis to identify the substructures in colibactin. These studies, coupled with isotope labeling and tandem MS analysis of colibactin-derived DNA interstrand cross-links, ultimately led to a structure assignment for the metabolite. We then discuss the ocimicides, plant secondary metabolites that were studied as agents against drug-resistant P. falciparum. We synthesized the core structure of the ocimicides and found significant discrepancies between our experimental NMR spectroscopic data and that reported for the natural products. We determined the theoretical carbon-13 NMR shifts for 32 diastereomers of the ocimicides. These studies indicated that a revision of the connectivity of the metabolites is likely needed. We end with some thoughts on the frontiers of secondary metabolite structure determination. As modern NMR computational methods are straightforward to execute, we advocate for their systematic use in validating the assignments of novel secondary metabolites.

Turning black to green: Circular economy of industrial carbon emissions

Industrial carbon emissions represent both a problem and an opportunity. As part of carbon capture and utilization (CCU) strategies, they can be used as raw materials to produce value-added products. Depending on the final product, the CCU approach could delay, reduce, or completely eliminate carbon emissions to the atmosphere. Although technically feasible, the barriers to commercial sustainability of such low-carbon or net-zero circular economy models are not sufficiently explored in the literature. To bridge this gap to a certain extent, I will discuss five key areas where circular economy-based CCU ecosystems producing net-zero synthetic fuels face challenges: supply-chain security, value-chain innovation, stakeholder cooperation, supply–demand market dynamics, and policy and regulation. To overcome some of these challenges, I will share opinions on how collaboration between government, private investors, and industries could help in developing relevant policies to close cost gaps in the short- and medium-term. Finally, I will explain how public–private partnership models could be used to pool resources, share risks, and how regulatory de-risking could be used to promote alignment between regulation and private investor for circular economy-based CCU projects for producing net-zero methanol.

Modulating the Interlayer Stacking of Covalent Organic Frameworks for Efficient Acetylene Separation.

Controllable modulation of the stacking modes of 2D (two-dimensional) materials can significantly influence their properties and functionalities but remains a formidable synthetic challenge. Here, an effective strategy is proposed to control the layer stacking of imide-linked 2D covalent organic frameworks (COFs) by altering the synthetic methods. Specifically, a modulator-assisted method can afford a COF with rare ABC stacking without the need for any additives, while solvothermal synthesis leads to AA stacking. The variation of interlayer stacking significantly influences their chemical and physical properties, including morphology, porosity, and gas adsorption performance. The resultant COF with ABC stacking shows much higher C2 H2 capacity and selectivity over CO2 and C2 H4 than the COF with AA stacking, which is not demonstrated in the COF field yet. Furthermore, the outstanding practical separation ability of ABC stacking COF is confirmed by breakthrough experiments of C2 H2 /CO2 (50/50, v/v) and C2 H2 /C2 H4 (1/99, v/v), which can selectively remove C2 H2 with good recyclability. This work provides a new direction to produce COFs with controllable interlayer stacking modes.

Construction of C–X (X = S, O, Se) Bonds via Lewis Acid-Promoted Functionalization of Trifluoromethylarenes

The conversion of easily available trifluoromethylarenes through C–F bond activation provides an attractive pathway for rapid access to difluorobenzylic substructures in producing pharmaceuticals and agrochemicals. However, recent advances in this area have been confined to C–C(H) bond construction, thus limiting the diversity of the accessible motifs. In contrast, the selective formation of a carbon–heteroatom bond via C–F bond functionalization, which enable fast and convenient access to diverse fluorine-containing motifs with high chemical diversity, remains a formidable synthetic challenge. Herein, we disclosed a Lewis acid promoted photoredox-catalyzed strategy for the construction of C–X (X = S, O or Se) bonds by single C(sp3)–F bond activation of trifluoromethylarenes, which enable the direct synthesis of medicinally interesting aryldifluoromethyl ether [ArCF2X– (X = S, O, or Se)] scaffolds. This method relies on readily available reagents and can tolerate a range of thiol, phenol, and selenol nucleophiles. Its utility was exemplified in the late-stage modifications of several pharmaceutical ingredients. Preliminary studies suggest two parallel pathways: a photocatalytic single electron-transfer (SET), and an electron donor–acceptor (EDA) process.

Total Syntheses of Polyhydroxylated Steroids by an Unsaturation-Functionalization Strategy.

Highly oxygenated cardiotonic steroids such as ouabain possess a wide spectrum of biological functions and remain significant synthetic challenges. Herein we have applied an unsaturation-functionalization strategy and developed a synthetic method in addressing the C19-hydroxylation issue for efficient synthesis of polyhydroxylated steroids. An effective asymmetric dearomative cyclization allowed the construction of the C19-hydroxy unsaturated steroidal skeleton in only 4 steps from the Hajos-Parrish ketone ketal 7. A synthetic sequence featured C3-OH directed hydrogenation/epoxidation, m-CPBA triggered epoxidation/S N 2' nucleophilic substitution, Birch reduction of enone, and regioselective LiAlH4 reduction furnished the polyhydroxy functionalities on the steroid skeleton in high stereochemical control and efficiency, which has ultimately enabled thetotal synthesis of 19-hydroxysarmentogenin and ouabagenin in 18 and 19 overall steps, respectively. The syntheses of these polyhydroxylated steroids has offered synthetic versatility and practicality in search for new therapeutic agents.

Total Syntheses of Polyhydroxylated Steroids by an Unsaturation‐Functionalization Strategy

AbstractHighly oxygenated cardiotonic steroids, such as ouabain, possess a wide spectrum of biological functions and remain significant synthetic challenges. Herein, we have applied an unsaturation‐functionalization strategy and developed a synthetic method in addressing the C19‐hydroxylation issue for efficient synthesis of polyhydroxylated steroids. An effective asymmetric dearomative cyclization allowed the construction of the C19‐hydroxy unsaturated steroidal skeleton in only four steps from the Hajos‐Parrish ketone ketal 7. The synthetic sequence featured C3−OH‐directed hydrogenation/epoxidation, m‐CPBA‐triggered epoxidation/SN2′ nucleophilic substitution, Birch reduction of an enone, and regioselective LiAlH4 reduction to furnish the polyhydroxy functionalities on the steroid skeleton with high stereochemical control and efficiency. This approach ultimately enabled the total synthesis of 19‐hydroxysarmentogenin and ouabagenin in 18 and 19 steps, respectively, overall. The synthesis of these polyhydroxylated steroids offers synthetic versatility and practicality in the search for new therapeutic agents.

Ultrathin Co-N-C Layer Modified Pt-Co Intermetallic Nanoparticles Leading to a High-Performance Electrocatalyst toward Oxygen Reduction and Methanol Oxidation.

The development of low platinum-based alloy electrocatalysts is crucial to accelerate the commercialization of fuel cells, yet remains a synthetic challenge and an incompatibility between activity and stability. Herein, a facile procedure to fabricate a high-performance composite that comprises Pt-Co intermetallic nanoparticles (IMNs) and Co, N co-doped carbon (Co-N-C) electrocatalyst is proposed. It is prepared by direct annealing of homemade carbon black-supported Pt nanoparticles (Pt/KB) covered with a Co-phenanthroline complex. During this process, most of Co atoms in the complex are alloyed with Pt to form ordered Pt-Co IMNs, while some Co atoms are atomically dispersed and doped in the framework of superthin carbon layer derived from phenanthroline, which is coordinated with N to form Co-Nx moieties. Moreover, the Co-N-C film obtained from complex is observed to cover the surface of Pt-Co IMNs, which prevent the dissolution and agglomeration of nanoparticles. The composite catalyst exhibits high activity and stability toward oxygen reduction reactions (ORR) and methanol oxidation reactions (MOR), delivering outstanding mass activities of 1.96 and 2.92 A mgPt -1 for ORR and MOR respectively, owing to the synergistic effect of Pt-Co IMNs and Co-N-C film. This study may provide a promising strategy to improve the electrocatalytic performance of Pt-based catalysts.

Development and Validation of a Targeted Treatment for Brain Tumors Using a Multi-Drug Loaded, Relapse-Resistant Polymeric Theranostic.

This study aimed to develop a multifunctional polymer platform that could address the issue of treatment resistance when using conventional chemotherapeutics to treat glioblastoma (GBM). An antibody-conjugated, multi-drug loaded hyperbranched polymer was developed that provided a platform to evaluate the role of targeted nanomedicine treatments in overcoming resistant GBM by addressing the various complications with current clinically administered formulations. The polymer was synthesized via reversible addition fragmentation chain transfer polymerization and included the clinical first-line alkylating agent temozolomide (TMZ) which was incorporated as a polymerizable monomer, poly (ethylene glycol) (PEG) units to impart biocompatibility and enable conjugation with αPEG-αEphA2 bispecific antibody (αEphA2 BsAb) for tumor targeting, and hydrazide moieties for attachment of a secondary drug which allows exploration of synergistic therapies. To overcome the resistance to TMZ, the O6 alkylguanine DNA alkyltransferase (AGT, DNA repair protein) inhibitor, dialdehyde O6 benzylguanine (DABG) was subsequently conjugated to the polymer via an acid labile hydrazone linker to facilitate controlled release under conditions encountered within the tumor microenvironment. The prolonged degradation half-life (4-5 h) of the polymer conjugated TMZ in vitro offered a potential avenue to overcome the inability to deliver these drugs in combination at therapeutic doses. Although only 20% of DABG could be released within the studied timeframe (192 h) under conditions mimicking the acidic nature of the tumor environment, cytotoxicity evaluation using cell assays confirmed the improved therapeutic efficacy toward resistant GBM cells after attaching DABG to the polymer delivery vehicle. Of note, when the polymeric delivery vehicle was specifically targeted to receptors (Ephrin A2) on the surface of the GBM cells using our in-house developed EphA2 specific BsAb, the dual-drug-loaded polymer exhibited an improved therapeutic effect on TMZ-resistant cells compared to the free drug combination. Both in vitro and in vivo targeting studies showed high uptake of the construct to GBM tumors with an upregulated EphA2 receptor (T98G and U251) compared to a tumor that had low expression (U87MG), where a dual tumor xenograft model was used to demonstrate the enhanced accumulation in tumor tissue in vivo. Despite the synthetic challenges of developing systems to effectively deliver controlled doses of TMZ and DABG, these studies highlight the potential benefit of this formulation for delivering multi-drug combinations to resistant GBM tumor cells and offer a platform for future optimization in therapeutic studies.

Immobilizing Metal Nanoparticles on Hierarchically Porous Organic Cages with Size Control for Enhanced Catalysis

Incorporating metal nanoparticles (MNPs) into porous composites with controlled size and spatial distributions is beneficial for a broad range of applications, but it remains a synthetic challenge. Here, we present a method to immobilize a series of highly dispersed MNPs (Pd, Ir, Pt, Rh, and Ru) with controlled size (<2 nm) on hierarchically micro- and mesoporous organic cage supports. Specifically, the metal-ionic surfactant complexes serve as both metal precursors and mesopore-forming agents during self-assembly with a microporous imine cage CC3, resulting in a uniform distribution of metal precursors across the resultant supports. The functional heads on the ionic surfactants as binding sites, together with the nanoconfinement of pores, guide the nucleation and growth of MNPs and prevent their agglomeration after chemical reduction. Moreover, the as-synthesized Pd NPs exhibit remarkable activity and selectivity in the tandem reaction due to the advantages of ultrasmall particle size and improved mass diffusion facilitated by the hierarchical pores.

Chemistry and Applications of Functionalized 2,4‐Thiazolidinediones

AbstractThiazolidinedione (TZD) is one of the privileged heterocyclic rings and has shown many biological applications in medicinal chemistry and drug discovery. This review covers the synthetic approaches of TZD and its derivatives, different synthetic techniques for affording the desired regioselectivity and stereoselectivity, and the techniques that would enhance reaction conditions such as microwave, one‐pot, or ultrasound synthesis. It focuses on synthetic challenges of glitazones and the transformation of other heterocycles to TZD. Moreover, the chemical and biological behavior of TZD through the substitution in the N3 position, modification of the C5 position, annealing in complex heterocyclic systems, and hybridization with other pharmacologically attractive moieties are discussed. All reactions mentioned are provided as possible with different reaction conditions, mechanisms, derivatives scope, yield and clarified by applications of such reactions in the construction of potential medicinal agents. The review also answers questions about rapid racemization of glitazones, their toxicity, considering TZD as pan‐assay interference compounds (PAINS) or not, and the influence of saturation of 5‐position of TZD in their biological activities. This review is a comprehensive guide to make informed decisions for construction of TZD derivatives with biological potentials.

Infinitenes as the Most Stable Form of Cycloarenes: The Interplay among π Delocalization, Strain, and π-π Stacking.

The recent successful preparation of infinitene has sparked widespread attention due to its aesthetic appeal and synthetic challenge. Spectroscopic measurements and follow-up computational investigations suggest that infinitene holds fundamental significance and potential applications in chiroptics, optoelectronics, asymmetric synthesis, and supramolecular chemistry. However, unlike other looped polyarenes enriched with sizes and shapes, the infinitene molecule seems, so far, the only known example of this fascinating new form of nanocarbons, whose further exploitation would be considerably limited because of the lack of molecular diversity. Here, we introduce a whole new family of generalized infinitenes with different sizes and topologies. Three types of infinitene structures are rationally designed by joining two units of coronene, kekulene, or their extended analogs. The constructed molecules of varying sizes, each with a large number of possible topoisomers, are systematically studied by DFT calculations. Comprehensive analysis using a simple energy decomposition model uncovers that the stability of infinitenes is governed by the interplay among π delocalization, steric strain, and π-π stacking. While the first two factors are crucial to the stability of smaller infinitenes, the latter is the primary stabilizing interaction for larger infinitenes. Most importantly, we show that larger-sized infinitenes are actually the energetically most favorable form among all known looped polyarenes; their substantial thermodynamic stability surpassing that of circulenes, various carbon nanobelts, and kekulene-like macrocycles renders them promising targets for synthesis. The simulated 1H NMR, UV-vis, and circular dichroism spectra along with optical rotations for the most stable infinitene species may help their identification in future synthetic efforts.