Five-membered Aromatic Heterocycles Research Articles

Isomorphic Fluorescent Nucleosides.

ConspectusIn 1960, Weber prophesied that "There are many ways in which the properties of the excited state can be utilized to study points of ignorance of the structure and function of proteins". This has been realized, illustrating that an intrinsic and highly responsive fluorophore such as tryptophan can alter the course of an entire scientific discipline. But what about RNA and DNA? Adapting Weber's protein photophysics prophecy to nucleic acids requires the development of intrinsically emissive nucleoside surrogates as, unlike Trp, the canonical nucleobases display unusually low emission quantum yields, which render nucleosides, nucleotides, and oligonucleotides practically dark for most fluorescence-based applications.Over the past decades, we have developed emissive nucleoside surrogates that facilitate the monitoring of nucleoside-, nucleotide-, and nucleic acid-based transformations at a nucleobase resolution in real time. The premise underlying our approach is the identification of minimal atomic/structural perturbations that endow the synthetic analogs with favorable photophysical features while maintaining native conformations and pairing. As illuminating probes, the photophysical parameters of such isomorphic nucleosides display sensitivity to microenvironmental factors. Responsive isomorphic analogs that function similarly to their native counterparts in biochemical contexts are defined as isofunctional.Early analogs included pyrimidines substituted with five-membered aromatic heterocycles at their 5 position and have been used to assess the polarity of the major groove in duplexes. Polarized quinazolines have proven useful in assembling FRET pairs with established fluorophores and have been used to study RNA-protein and RNA-small-molecule binding. Completing a fluorescent ribonucleoside alphabet, composed of visibly emissive purine (thA, thG) and pyrimidine (thU, thC) analogs, all derived from thieno[3,4-d]pyrimidine as the heterocyclic nucleus, was a major breakthrough. To further augment functionality, a second-generation emissive RNA alphabet based on an isothiazolo[4,3-d]pyrimidine core (thA, tzG, tzU, and tzC) was fabricated. This single-atom "mutagenesis" restored the basic/coordinating nitrogen corresponding to N7 in the purine skeleton and elevated biological recognition.The isomorphic emissive nucleosides and nucleotides, particularly the purine analogs, serve as substrates for diverse enzymes. Beyond polymerases, we have challenged the emissive analogs with metabolic and catabolic enzymes, opening optical windows into the biochemistry of nucleosides and nucleotides as metabolites as well as coenzymes and second messengers. Real-time fluorescence-based assays for adenosine deaminase, guanine deaminase, and cytidine deaminase have been fabricated and used for inhibitor discovery. Emissive cofactors (e.g., SthAM), coenzymes (e.g., NtzAD+), and second messengers (e.g., c-di-tzGMP) have been enzymatically synthesized, using xyNTPs and native enzymes. Both their biosynthesis and their transformations can be fluorescently monitored in real time.Highly isomorphic and isofunctional emissive surrogates can therefore be fabricated and judiciously implemented. Beyond their utility, side-by-side comparison to established analogs, particularly to 2-aminopurine, the workhorse of nucleic acid biophysics over 5 decades, has proven prudent as they refined the scope and limitations of both the new analogs and their predecessors. Challenges, however, remain. Associated with such small heterocycles are relatively short emission wavelengths and limited brightness. Recent advances in multiphoton spectroscopy and further structural modifications have shown promise for overcoming such barriers.

An overview of imidazole and its analogues as potent anticancer agents.

The quest for novel, physiologically active imidazoles remains an exciting topic of research among medicinal chemists. The imidazole ring is a five-membered aromatic heterocycle that is found in both natural and synthesized compounds. Multiple anticancer drug classes are currently available on the market, but concerns including toxicity, limited efficacyand solubility have lowered the overall therapeutic index. Therefore, the hunt for new potential chemotherapeutic agents persists. The development of imidazole as a reliable and safer alternative to anticancer treatment is generating much attention among experts. Tubulin or microtubulepolymerization inhibition andchanges in the structure and function of DNA, VEGF, topoisomerase, kinases, histone deacetylasesand certain other proteins that affect gene expression are among the putative targets.

Recent advances of benzimidazole as anticancer agents.

Cancer is the second leading cause of death globally, with 9.6 million deaths yearly. As a life-threatening disease, it necessitates the emergence of new therapies. Resistance to current chemotherapies drives scientists to develop new medications that will eventually be accessible. Because heterocycles are so common in biological substances, compounds play a big part in the variety of medications that have been developed. The "Master Key" is the benzimidazole nucleus, which consists of a six-membered benzene ring fused with a five-membered imidazole/imidazoline ring, which is an azapyrrole. One of the five-membered aromatic nitrogen heterocycles identified in American therapies that have been approved by the Food and Drug Administration (FDA). Our results show that benzimidazole's broad therapeutic spectrum is due to its structural isosteres with purine, which improves hydrogen bonding, electrostatic interactions with topoisomerase complexes, intercalation with DNA, and other functions. It also enhances protein and nucleic acid inhibition, tubulin microtubule degeneration, apoptosis, DNA fragmentation, and other functions. Additionally, readers for designing the more recent benzimidazole analogues as prospective cancer treatments.

Synthesis, insecticidal activity and stability study of novel nitromethylene neonicotinoids with five-membered aromatic heterocycles

Twenty-four novel neonicotinoid analogues with nitromethylene and five-membered aromatic heterocycles were designed and synthesized. All target molecular structures have been confirmed by analytical and spectral data. Some compounds exhibited notable insecticidal activities against aphid (Aphis medicaginis) and brown planthopper (Nilaparvata lugens). The aqueous stability test confirmed that the stabilities of those compounds were superior to the leading compound, and the photostability was even better than that of imidacloprid.

Discovery of 8-Hydroxyquinoline as a Histamine Receptor 2 Blocker Scaffold.

Histamine receptor 2 (HRH2) activation in the stomach results in gastric acid secretion, and HRH2 blockers are used for the treatment of peptidic ulcers and acid reflux. Over-the-counter HRH2 blockers carry a five-membered aromatic heterocycle, with two of them additionally carrying a tertiary amine that decomposes to N-nitrosodimethylamine, a human carcinogen. To discover a novel HRH2 blocker scaffold to serve in the development of next-generation HRH2 blockers, we developed an HRH2-based sensor in yeast by linking human HRH2 activation to cell luminescence. We used the HRH2-based sensor to screen a 403-member anti-infection chemical library and identified three HRH2 blockers, chlorquinaldol, chloroxine, and broxyquinoline, all sharing an 8-hydroxyquinoline scaffold, which is not found among known HRH2 antagonists. Critically, we validate their HRH2-blocking ability in mammalian cells. Molecular docking suggests that the HRH2 blockers bind the histamine binding pocket and structure–activity data point toward these blockers acting as competitive antagonists. Chloroxine and broxyquinoline are antimicrobials that can be found in the gastrointestinal tract at concentrations that would block HRH2, thus likely modulating gastric acid secretion. Taken together, this work demonstrates the utility of GPCR-based sensors for rapid drug discovery applications, identifies a novel HRH2 blocker scaffold, and provides further evidence that antimicrobials not only target the human microbiota but also the human host.

DFT insights into the adsorption mechanism of five-membered aromatic heterocycles containing N, O, or S on Fe(1 1 0) surface

Understanding the interaction of five-membered aromatic heterocycles with Fe(110) surface is crucial to the design of novel inhibitors against the corrosion of iron and steel. Herein, we report a detailed study of the adsorption properties and the bonding mechanism of pyrrole, furan, and thiophene on Fe(110) surface employing density functional theory (DFT) calculations. In the most stable adsorption geometries, the adsorbates lie flat at the hollow site and form covalent bonds with surface Fe atoms. The chemisorptions are demonstrated by large adsorption energies and charge transfers from Fe(110) to the adsorbates. Taking vdW corrections into account in the DFT calculations has a minimal effect on the adsorption geometries whereas it significantly increases the adsorption energies. The energetic and structural analysis demonstrates large molecular distortion induced by the adsorbate–surface interaction, and thiophene experiences the least molecular distortions, thereby having the largest adsorption energy among the adsorbates. The electronic structure analysis reveals that the electronic interactions of pyrrole, furan, and thiophene and Fe(110) are due to the overlaps of the frontier molecular orbitals with Fe-3dz2 and Fe-(3dxz + 3dyz) states. The charge transfer between the adsorbates and Fe(110) are elucidated by the charge density difference plot and Bader charge analysis.

1,3,4-thiadiazole: a privileged scaffold for drug design and development.

1,3,4-thiadiazole is a five-membered aromatic heterocycle containing two nitrogen atoms and one sulfur atom. As a privileged scaffold, it has its unique chemical properties and biological characteristics. In the design of drugs, they are widely and flexibly applied by medicinal chemists, and many candidates with therapeutic prospects have been developed. In this review, we focus on 1,3,4-thiadiazole derivatives and their various biological activities reported in the past five years (from 2015 to early 2020), such as anticancer, antibacterial, antifungal, anti-tuberculosis, anti-inflammatory, antivirus, anti-leishmania and other functions. It is believed that this review can provide some new ideas for seeking rational design to develop 1,3,4-thiadiazole based medicinal agents with better activity and lower toxicity.

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms

Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in assembling information about fused five-membered aromatic heterocycles, and after having presented mono-hetero-atomic five-membered aromatic heterocycles in Part I. The current review Part II is intended to present an overview of the different synthetic routes to coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring, covering the literature from 1945 to 2021.

Deciphering Benzene–Heterocycle Stacking Interaction Impact on the Electronic Structures and Photophysical Properties of Tetraphenylethene-Cored Foldamers

Open AccessCCS ChemistryRESEARCH ARTICLE1 Jan 2022Deciphering Benzene–Heterocycle Stacking Interaction Impact on the Electronic Structures and Photophysical Properties of Tetraphenylethene-Cored Foldamers Zeyan Zhuang, Pingchuan Shen, Jianqing Li, Jinshi Li, Zujin Zhao and Ben Zhong Tang Zeyan Zhuang State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, SCUT-HKUST Joint Research Institute, South China University of Technology, Guangzhou 510640 Google Scholar More articles by this author , Pingchuan Shen State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, SCUT-HKUST Joint Research Institute, South China University of Technology, Guangzhou 510640 Google Scholar More articles by this author , Jianqing Li State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, SCUT-HKUST Joint Research Institute, South China University of Technology, Guangzhou 510640 Google Scholar More articles by this author , Jinshi Li State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, SCUT-HKUST Joint Research Institute, South China University of Technology, Guangzhou 510640 Google Scholar More articles by this author , Zujin Zhao *Corresponding author: E-mail Address: [email protected] State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, SCUT-HKUST Joint Research Institute, South China University of Technology, Guangzhou 510640 Google Scholar More articles by this author and Ben Zhong Tang State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, SCUT-HKUST Joint Research Institute, South China University of Technology, Guangzhou 510640 Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077 AIE Institute, Guangzhou Development District, Huangpu, Guangzhou 510530 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202000677 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Conjugation, as an essential chemical term used to describe electron delocalization, can be roughly grouped into two categories, through-bond conjugation (TBC) and through-space conjugation (TSC). A hybrid conjugation system integrating both TBC and TSC is rarely studied and utilized, for lack of a well-established model and difficulty of structure modification and property tuning, despite its theoretical significance and potential applications. Herein, various foldamers with a tetraphenylethene (TPE) core are employed as hybrid conjugation models to investigate structure–property correlation by introducing heterocycles of furan/thiophene into the π-stacking TSC component. For comparison, two kinds of TPE-cored foldamers with different stacking models, a benzene–heterocycle stacking model and a benzene–benzene stacking model, are designed. Combining experimental measurements and theoretical calculations, the impact of benzene–heterocycle interaction on the hybrid conjugation natures and photophysical properties has been studied systematically. The results reveal that the benzene–heterocycle stacking model can fabricate a hybrid conjugation nature with an improved TSC component to make a more dominant contribution to the electronic transition natures than the benzene–benzene stacking model, leading to the distinguishing photophysical behavior. This work provides valuable guidance for the design of new functional materials with hybrid conjugation systems. Download figure Download PowerPoint Introduction Conjugation, referring to the stabilizing interaction between/among local orbitals, is an essential term used to describe the electronic consequence of electron delocalization,1–3 which plays a fundamental role in the organic chemical field relating particularly to organic electronics and photonics.4,5 Considering the different orbital interaction patterns, conjugation can be conceptually partitioned into through-bond and -space categories.6–9 Since the first report on conducting polyacetylenes in 1977 molecules with through-bond conjugation (TBC),10 have been extensively studied and developed from mechanism to application.11–13 Additionally, the study of through-space conjugation (TSC), or the spatial electron delocalization based on noncovalent overlapped orbitals, has made decent progress, for instance with the development of the representative TSC model of cyclophane.14–17 Yet the monotonous model once limited extended research on TSC in both fundamental and applied aspects, further leading to the uncoordinated developments of TBC and TSC, each going at their own pace. Gradually, various types of molecular scaffolds aided by π–π stacking interaction18–20 have joined the ranks of the TSC category successively, such as polybenzofulvene,21,22 bicyclo[4.4.1]undecanone,23,24 xanthene,25,26 tertiary diarylurea,27,28 iptycene,29,30 and so forth.31–33 These interesting molecules have driven remarkable progress, not only in the understanding of the electronic nature of TSC (i.e., its charge stabilization and transport, structure–property correlation)34,35 but also in terms of its high-tech applications, such as in molecular electronics.36,37 Sequentially, integrating TBC and TSC into a hybrid conjugation system, where multiple relationships of interdependence, complementarity, cooperation, and competition exist between TBC and TSC, has come to the forefront. More recently, diverse hybrid conjugation architectures based on naphthalene,38,39 hexaarylbenzene,40,41ortho-arylenes,42,43 helicenes,44,45 and so forth have been explored by chemists. Their emergence offers a promising platform for building novel multidimensional functional materials. Simultaneously, an urgent demand for a theoretical system has arisen to achieve the predictability and controllability of a hybrid conjugation system. However, blocked by the following difficulties, few efforts have been devoted to this problem. For a vested hybrid conjugation framework, the geometrical scaffold is quite strict, and the building blocks are limited, which make the structure modification difficult and inflexible. Hence, the modulation of electric structure and the broad-range tuning of properties are blocked. Another challenge lies in the rational decomposition and analysis of the TBC and TSC components in a complex hybrid conjugation system to decipher the effect of electric structure on the property, further hindering the establishment of a structure–property correlation. In previous work, we established a new class of hybrid conjugation system of tetraphenylethene (TPE)-cored foldamers, which employ TPE as a TBC core and fold a pair of aryl wings (fragments or chains) into a π-stacking TSC component.46–49 Utilizing such a fantastic geometry, efficient luminescent materials, bipolar carrier transporting materials,50 and multichannel single-molecular wires51,52 have been successfully created. In addition, preliminary investigations on the structure–property correlation have been carried out. The results reveal that these TPE-cored foldamers follow a certain pattern on luminescence behaviors determined by the central folded fragments with strict geometries.53 Only by introducing strong electron-donating/-withdrawing groups, like fluoroborate anions54 or protonated pyridine,55 into the folded fragments, can their emission origin be tuned into the intramolecular charge-transfer (ICT) state, partially due to the altered TSC attributes. With the underpinning of upfront efforts, in this work, we select TPE-cored foldamers as models to further dig into the structural modulation and property tuning of the hybrid conjugation system. In addition, to enrich the building blocks, beyond the widely used aromatic hydrocarbons in TSC and hybrid conjugation systems, the heterocyclic furan,56,57 and thiophene58,59 grab our attention, which have been extensively adopted in TBC materials but barely noticed in the construction of TSC/hybrid conjugation materials.60–62 As five-membered aromatic heterocycles, furan and thiophene have homologous characteristics of π-electron excessiveness and high structural planarity and rigidity.63,64 By comparison, furan is electron-richer but less aromatic than thiophene due to its smaller covalent radius but higher electronegativity of oxygen than sulfur, which leads to higher electrophilic reactivity and better structural rigidity and planarity (smaller torsional angle and greater quinoid character) of furan. Nevertheless, it allows a larger propensity for thiophene-containing conjugates to form weak interaction-based conformational locking to improve rigidity and planarity.65,66 Furan and thiophene are introduced into the π-stacking TSC component of TPE-cored foldamers, aiming to enhance the TSC contribution (with settled central TBC skeleton) and further modulate the hybrid conjugation nature, as indicated in Scheme 1. In addition, to better investigate the impact of π-stacking patterns on the hybrid conjugation nature of TPE-cored foldamers, two different kinds of stacking models, a benzene–heterocycle stacking model and a benzene–benzene stacking model, are designed by means of adjusting the conjugation lengths and bonding positions of the stacked fragments containing furan, thiophene, benzo[b]furan, or benzo[b]thiophene. Systematic studies are conducted based on the experimental investigations of crystal structures and photophysical behaviors as well as theoretical calculations on both ground and excited states. The results reveal that foldamers with a benzene–benzene stacking model, relative to those with a benzene–benzene stacking model, have better TBC of each fragment, stronger TSC between the two stacked fragments, and an additional TSC component of Xa/Ca–vinyl. These variations of the hybrid conjugation nature suggest that the vinyl-linked stacked fragments with distinct TSC character, rather than the central TPE part, make a dominant contribution to the electronic transition natures, leading to their distinguishing photophysical behaviors of different absorption profiles, decreased emission efficiencies, slight solvatochromic effects, short emission lifetimes, and unique temperature-dependent emissions. Scheme 1 | Design strategy and molecular structures of new TPE-cored foldamers. Download figure Download PowerPoint Experimental Methods Synthesis and characterization (Z)-1,2-Bis(2-(furan-2-yl)phenyl)-1,2-diphenylethene (f-TPE-Fu) To a mixture of 2-phenylmethanone derivatives (8 mmol) and zinc dust (1.15 g, 17.6 mmol) in 60 mL dry tetrahydrofuran (THF) was added dropwise TiCl4 (0.97 mL, 1.67 g, 8.8 mmol) under nitrogen at –78 °C. After stirring for 15 min at –78 °C, the reaction mixture was warmed to room temperature (RT) for stirring another 15 min and then heated to reflux overnight. The mixture was quenched with saturated Na2CO3 solution and filtrated. The filtrate was extracted with dichloromethane (DCM) three times. After solvent evaporation, the residue was purified by silica-gel column chromatography using hexane as eluent. The crude product collected from chromatography was further crystallized by slow solvent diffusion and evaporation using a hexane/DCM mixture. Faint yellow and transparent crystals of f-TPE-Fu were obtained in yield 32% (0.59 g). 1H NMR (500 MHz, CD2Cl2, δ) [trimethylsilane (TMS), ppm]: 7.46 (d, J = 1.5 Hz, 2H), 7.35 (dd, J = 7.5, 1.0 Hz, 2H), 7.11–7.03 (m, 12H), 6.94–6.90 (m, 2H), 6.71 (dd, J = 8.0, 1.0 Hz, 2H), 6.58 (d, J = 3.5 Hz, 2H), 6.40 (m, 2H). 13C NMR (125 MHz, CDCl3, δ) (TMS, ppm): 153.9, 142.2, 141.5, 140.6, 138.8, 131.4, 130.7, 130.2, 127.5, 126.9, 126.7, 126.7, 126.4, 111.4, 107.5. High-resolution mass spectrometry (HRMS) (m/z) M+ calcd for C34H24O2, 464.1776; found, 464.1775. (Z)-1,2-Diphenyl-1,2-bis(2-(thiophene-2-yl)phenyl)ethane (f-TPE-Th) The procedure was analogous to that described for f-TPE-Fu. Colorless and transparent crystals were obtained in yield 27% (0.50 g). 1H NMR (500 MHz, CD2Cl2, δ) (TMS, ppm): 7.23–7.17 (m, 4H), 7.07–7.01 (m, 12H), 6.97–6.94 (m, 2H), 6.93–6.89 (m, 2H), 6.83–6.78 (m, 2H), 6.24 (dd, J = 7.5, 1.0 Hz, 2H). 13C NMR (125 MHz, deuterated acetone, δ) (TMS, ppm): 145.1, 144.8, 143.0, 140.5, 135.5, 133.2, 132.7, 131.2, 129.3, 128.7, 128.7, 128.7, 128.2, 127.6, 126.9. HRMS (m/z): M+ calcd for C34H24S2, 496.1319; found, 496.1299. (Z)-1,2-Bis(4′-(furan-2-yl)-[1,1′-biphenyl]-2-yl)-1,2-diphenylethene (f-TPE-PFu) The procedure was analogous to that described for f-TPE-Fu except for the final crystallization. White powders were directly obtained after chromatography in 68% yield (1.68 g). 1H NMR (400 MHz, CD2Cl2, δ) (TMS, ppm): 7.54 (d, J = 8.4 Hz, 4H), 7.48 (d, J = 1.2 Hz, 2H), 7.22 (d, J = 8.0 Hz, 4H), 7.14–7.02 (m, 14H), 6.74–6.69 (m, 2H), 6.66 (d, J = 3.6 Hz, 2H), 6.50–6.47 (m, 2H), 5.78 (d, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3, δ) (TMS, ppm): 154.1, 144.8, 141.9, 141.0, 140.7, 140.6, 138.7, 132.6, 131.4, 129.3, 129.1, 128.9, 127.6, 127.2, 126.7, 126.4, 123.3, 111.7, 104.7. HRMS (m/z): M+ calcd for C46H32O2, 616.2402; found 616.2435. (Z)-1,2-Diphenyl-1,2-bis(4′-(thiophene-2-yl)-[1,1′-biphenyl]-2-yl)ethane (f-TPE-PTh) The procedure was analogous to that described for f-TPE-PFu. White powders were obtained in 62% yield (1.61 g). 1H NMR (500 MHz, CD2Cl2, δ) (TMS, ppm): 7.47 (d, J = 8.0 Hz, 4H), 7.30–7.27 (m, 2H), 7.27 (dd, J = 5.0, 1.5 Hz, 2H), 7.18 (d, J = 8.2 Hz, 4H), 7.12–7.00 (m, 16H), 6.75–6.69 (m, 2H), 5.82 (d, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3, δ) (TMS, ppm): 144.8, 144.5, 140.9, 140.9, 140.5, 138.8, 132.6, 132.4, 131.4, 129.3, 129.2, 128.0, 127.6, 127.2, 126.8, 126.4, 125.3, 124.6, 122.8. HRMS (m/z): M+ calcd for C46H32S2, 648.1945; found, 648.1957. (Z)-1,2-Bis(2-(benzofuran-2-yl)phenyl)-1,2-diphenylethene (f-TPE-[2]BFu) The procedure was analogous to that described for f-TPE-Fu. Faint yellow and transparent crystals were obtained in yield 28% (0.63 g). 1H NMR (500 MHz, CD2Cl2, δ) (TMS, ppm): 7.57–7.47 (m, 6H), 7.30–7.24 (m, 2H), 7.23–7.11 (m, 8H), 7.07–7.01 (m, 6H), 6.91 (s, 2H), 6.86–6.80 (m, 2H), 6.63 (d, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CD2Cl2, δ) (TMS, ppm): 156.0, 154.6, 142.4, 141.4, 138.8, 131.7, 130.9, 129.8, 129.2, 127.8, 127.8, 127.6, 126.9, 126.5, 124.0, 122.6, 120.8, 111.1, 103.9. HRMS (m/z): M+ calcd for C42H28O2, 564.2089; found, 564.2103. (Z)-1,2-Bis(2-(benzo[b]thiophene-2-yl)phenyl)-1,2-diphenylethene (f-TPE-[2]BTh) The procedure was analogous to that described for f-TPE-Fu. Colorless and transparent crystals were obtained in yield 23% (0.55 g). 1H NMR (500 MHz, CD2Cl2, δ) (TMS, ppm): 7.79 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.34–7.24 (m, 6H), 7.19–7.01 (m, 14H), 6.66–6.59 (m, 2H), 6.11 (d, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CD2Cl2, δ) (TMS, ppm): 143.8, 143.6, 141.6, 140.3, 140.2, 139.0, 133.7, 132.0, 131.3, 130.0, 127.8, 127.7, 127.2, 126.6, 124.2, 124.0, 123.4, 122.5, 122.0. HRMS (m/z): M+ calcd for C42H28S2, 596.1632; found, 596.1588. (Z)-1,2-Bis(2-(benzofuran-5-yl)phenyl)-1,2-diphenylethene (f-TPE-[5]BFu) The procedure was analogous to that described for f-TPE-PFu. White powders were obtained in 52% yield (1.17 g). 1H NMR (500 MHz, CD2Cl2, δ) (TMS, ppm): 7.61 (d, J = 2.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.25–7.18 (m, 4H), 7.10–7.00 (m, 14H), 6.72 (d, J = 1.0 Hz, 2H), 6.56–6.49 (m, 2H), 5.45 (d, J = 8.0 Hz, 2H). 13C NMR (125 MHz, CDCl3, δ) (TMS, ppm): 171.2, 154.0, 145.0, 141.3, 141.2, 138.9, 136.6, 132.5, 131.4, 129.9, 127.5, 127.3, 126.7, 126.3, 126.3, 125.6, 121.5, 110.2, 106.7. HRMS (m/z): M+ calcd for C42H28O2, 564.2089; found, 564.2088. (Z)-1,2-Bis(2-(benzo[b]thiophene-5-yl)phenyl)-1,2-diphenylethene (f-TPE-[5]BTh) The procedure was analogous to that described for f-TPE-PFu. White powders were obtained in 57% yield (1.36 g). 1H NMR (500 MHz, CD2Cl2, δ) (TMS, ppm): 7.76 (d, J = 8.5 Hz, 2H), 7.45–7.39 (d, J = 5.6 Hz, 4H), 7.31 (dd, J = 8.5, 1.0 Hz, 2H), 7.25 (d, J = 5.5 Hz, 2H), 7.15–6.99 (m, 14H), 6.43–6.36 (m, 2H), 5.39 (d, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3, δ) (TMS, ppm): 145.1, 141.0, 140.9, 139.9, 138.8, 138.0, 137.8, 132.5, 131.4, 129.8, 127.6, 126.7, 126.6, 126.3, 126.1, 125.5, 124.1, 123.8, 121.3. HRMS (m/z): M+ calcd for C42H28S2, 596.1632; found, 596.1626. Theoretical calculations The ground- and excited-state geometries were optimized using the density functional theory (DFT) and time-dependent DFT (TD-DFT) method, respectively, with B3LYP-D3(BJ) hybrid functional at the basis set level of 6-311+G(d,p), performed by the Gaussian 16 software package (Gaussian, Inc., Wallingford, CT). No symmetry constraint was applied for optimization. The thermal corrected Gibbs free energies were calculated with a scale factor of 0.964. The independent gradient model (IGM), simulative absorption spectra, electron and hole analysis, and two-dimensional (2D) color-filled transition density matrix (TDM) maps were performed with Multiwfn 3.7 (Beijing Kein Research Center for Natural Sciences, Beijing, China).67 The nonadiabatic coupling matrix element (NACME) values were calculated using the TD-DFT method at the level of B3LYP-D3(BJ)/6-311+G(d,p) by the Gaussian 16 software package. The spin–orbit coupling (SOC) values were calculated using the TD-DFT method at the level of B3LYP-D3(BJ)/def2-TZVP, performed by ORCA 4.1.68 Results and Discussion Synthesis and characterization Synthesis The new TPE-cored foldamers are synthesized using typical McMurry coupling from 2-phenylmethanone derivatives in the presence of Zn and TiCl4 ( Supporting Information Scheme S1). f-TPE-PFu, f-TPE-PTh, f-TPE-[5]BFu, and f-TPE-[5]BTh with a benzene–benzene stacking model are easily obtained in moderate yields of 52−68% by column chromatography. But for f-TPE-Fu, f-TPE-Th, f-TPE-[2]BFu, and f-TPE-[2]BTh with a benzene–heterocycle stacking model, additional purification procedure of slow solvent diffusion and evaporation in hexane/DCM mixed solvents is required to gain the pure products as crystalline precipitates in yields of 23−32%. The detailed synthetic procedures and characterization data are given in the Experimental Methods section and Supporting Information. Crystal structure Analyzed by X-ray diffraction crystallography, the crystal structures of these TPE-cored foldamers shown in Figure 1 verify their expected folded cis-configurations, where two (bi)phenyl-(benzo)heterocycle fragments are aligned in an antiparallel face-to-face manner with certain displacement. To evaluate their folded geometries, some major structural parameters are labeled in Figure 1, and the detailed data are listed in Table 1. The shortest interplanar distances (d1) between two stacked aromatic rings are as short as 3.02–3.42 Å, which are shorter than the sum of van der Waals (vdW) radii of two carbon atoms (3.5 Å),18,69 indicating the presence of TSC between the two stacked fragments in both two kinds of stacking models. Since these stacked fragments with TSC are connected by a vinyl bridge, there are TBC characters as well, revealing that these foldamers hold a hybrid conjugation nature. Figure 1 | Crystal structures of new TPE-cored foldamers with indicated labels: d1 = the shortest interplanar distance between two stacked aromatic rings measured from point (carbon atom) to point (carbon atom); d2 = the distance from Xa/Ca atoms to the center of double bond; d3 = the distance from Ha atoms to the center of opposite aromatic ring; γ = crossing angle of the two stacked fragments; θ = the dihedral angle of two stacked aromatic rings; D1, D2 = interring torsion angle; L1, L2 = interring bond length. Note: two kinds of configuration are found in f-TPE-Th and f-TPE-[2]BTh. Download figure Download PowerPoint Table 1 | Crystal Structure Parameters (as Indicated in Figure 1) of New TPE-Cored Foldamers Compound d1, d1′ (Å) d2, d2′ (Å) d3, d3′ (Å) γ (deg) θ, θ′ (deg) |D1|, |D1′| (deg) |D2|, |D2′| (deg) L1, L1′ (Å) L2, L2′ (Å) f-TPE-Fu 3.42, 3.11 2.98, 3.09 3.23, 2.72 38.0 23.1, 21.4 30.4, 34.1 / 1.439, 1.425 / f-TPE-Tha 3.02, 3.02 3.22, 3.18 3.12, 3.12 4.9 4.7, 8.1 48.9, 44.8 / 1.445, 1.441 / 3.10, 3.04 3.16, 3.07 3.26, 3.16 0.5 10.4, 11.4 43.5, 42.3 / 1.429, 1.433 / f-TPE-PFu 3.22, 3.22 3.24, 3.24 3.21, 3.21 23.8 3.8, 3.8 44.6, 44.6 8.4, 11.1 1.489, 1.489 1.458, 1.458 f-TPE-PTh 3.20, 3.20 3.19, 3.19 3.10, 3.10 22.7 7.0, 7.0 42.1, 43.9 16.8, 16.8 1.474, 1.474 1.462, 1.462 f-TPE-[2]BFu 3.29, 3.16 2.84, 3.16 3.10, 3.00 22.1 32.1, 18.4 17.4, 29.8 / 1.447, 1.462 / f-TPE-[2]BTha 3.26, 3.23 3.20, 3.26 3.15, 3.27 16.3 20.4, 18.8 33.5, 35.4 / 1.449, 1.441 / 3.24, 3.21 3.09, 3.20 3.17, 3.03 10.9 17.7, 19.4 36.2, 35.4 / 1.485, 1.481 / f-TPE-[5]BFu 3.18, 3.17 3.18, 3.16 3.12, 3.10 15.1 7.7, 8.3 50.4, 49.6 / 1.490, 1.477 / f-TPE-[5]BTh 3.32, 3.30 3.23, 3.14 3.11, 2.87 16.3 14.0, 20.5 47.5, 44.2 / 1.493, 1.485 / aTwo kinds of configurations are found in f-TPE-Th and f-TPE-[2]BTh. The data in the top line correspond to the configuration with both heteroatoms pointing toward the inside of the molecule, and the data in the bottom line correspond to the configuration with both heteroatoms pointing toward the outside of the molecule. The misaligned dispositions of the two stacked fragments can be assessed by the crossing angle of the two stacked fragments (γ) and the dihedral angles of two stacked aromatic rings (θ). Compared with the fragments in the benzene–benzene stacking model that possess moderate crossing angles (γ = 15.1–23.8°) and slightly tilted interplane angles (θ = 3.8–20.5°), those in benzene–furan stacking model are located in the most misaligned disposition with γs in the range of 22.1–38.0° and θs in the range of 18.4–32.1°. And those in the benzene–thiophene stacking model adopt a decent arrangement with smaller crossing angles (γ = 0.5–16.3°) and larger dihedral angles (θ = 4.7–20.4°). These are the composite architectural outcomes presumably overdetermined by the intramolecular electronic and geometrical relationship. On the one hand, the electrostatic repulsion between two stacked rings and the inhomogeneous electronic distribution of furan and thiophene ring are largely accountable for the staggered and tilted stacking manners of two fragments. On the other hand, the disposition of the two stacked fragments may be also associated with additional nonbonded interaction between the fragments and the central vinyl bridge with the distances (d2) ≤ 3.38 Å from the Xa/Ca atoms labeled in Figure 1 to the center of double bond. The d2s of Oa–vinyl are found to be the shortest ones (2.84–2.98 Å), and those of Sa–vinyl (3.18–3.26 Å) are close to those of Ca–vinyl (3.07–3.38 Å), which may be relevant to the vdW radii of the Xa/Ca atoms69 and also influenced by the Ca–H steric hindrance. This interaction ought to be given attention as a supplementary TSC in these hybrid conjugation systems, especially when the heteroatoms (Xa) in five-membered heterocycles point toward the central vinyl bridge without interference from C–H steric hindrance in benzene–heterocycle stacking model. In addition, the interring torsion angles (D1 or D2) of each (bi)phenyl-(benzo)heterocycle fragment, which are influenced by the electrostatic and steric repulsion of the opposite fragment, also have an impact on the inclination of two stacked rings in return. It can be found that |D1|s between furan and the adjacent bonded phenyl ring are the smallest (17.4–34.1°), those between thiophene and the adjacent bonded phenyl ring rank second (33.5–48.9°), and those between two bonded phenyl rings are the largest (42.1–50.4°), although they are much larger than |D2|s (8.4–16.8°) related to the unrestricted heterocycles. Besides, the interring bond lengths (L1 or L2) of each (bi)phenyl-(benzo)heterocycle fragment also correspond to the regularity of interring torsion angles. L1s between furan and the adjacent bonded phenyl ring are shortest (1.425–1.462 Å), those between thiophene and the adjacent bonded phenyl ring are the second (1.429–1.485 Å), and those between two bonded phenyl rings are the longest (1.474–1.493 Å), irrespective of the unrestricted heterocycles (L2 = 1.458–1.462 Å). These structural findings are attributed to the better planarity and rigidity of furan and thiophene rings, reflecting that the TBC degree of each fragment increases following the order of benzene−benzene < thiophene−benzene < furan−benzene. Hence, the fragments in the benzene–heterocycle stacking model possess larger TBC degree than those in the benzene–benzene stacking model, which ought to affect their formative TSC component. NMR spectrum Like other TPE-cored foldamers in the literature,46,53 these new foldamers also have the Ha protons labeled in Figure 1, which are found to overlie the opposite aromatic rings with the distances (d3) ≤ 3.26 Å from the Ha proton to the center of the opposite aromatic ring. These Ha protons are located within the magnetic shielded zone of the opposite aromatic rings, and thus authenticated by the distinctive doublet peaks in the 1H NMR spectra (marked in Supporting Information Figure S1), which are located at 5.4–6.6 ppm and notably upfield-shifted from the normal ranges for benzenoid compounds,70 suggesting that the folded cis-configurations are also tenable in solution. The distinctive peaks are recorded at ∼6.6 ppm in the benzene–furan stacking model and at ∼6.1 ppm in benzene–thiophene stacking model, which are shifted not as high as those in the benzene–benzene stacking model (∼5.4 ppm). Because the shielding effect derives from the diamagnetic ring current of aromatic rings,71 the degrees of upfield-shifts are well consistent with an enhancement in aromaticity of the aryl shields in the order furan < thiophene < benzene.72 Configuration analysis It is also noteworthy that, based on the crystal structures, the orientations of the heterocyclics in these TPE-cored foldamers are disorderly, that is, the heteroatoms may point toward the inside or the outside of the molecules. Hence, it is conceivable that there may exist three kinds of configurations for each foldamer as illustrated in Supporting Information Scheme S3, abbreviated as ii, io, and oo, respectively. However, only one or two conformer(s) is/are found in crystal structures. Geometry optimizations of the ground state (S0) are then performed at the B3LYP-D3(BJ)/6-311+G(d,p) level, based on the initial geometries of three possible conformers. Ultimately all kinds of stable conformations for each foldamer are obtained as expected, whose major parameters are listed in Supporting Information Table S1. Their general structural characteristics are largely consistent with the findings in crystal structures with better regularity. It can be observed that the architectural geometries of f-TPE-Fu, f-TPE-Th, f-TPE-[2]BFu, and f-TPE-[2]BTh with a benzene–heterocycle stacking model are affected more obviously by the orientations of the heterocyclics, in comparison with those of f-TPE-PFu, f-TPE-PTh, f-TPE-[5]BFu, and f-TPE-[5]BTh with a benzene–benzene stacking model. This distinction is primarily determined by the Xa/Ca atoms interacting with the central vinyl bridge. For the benzene–heterocycle stacking model, the d2s of Xa/Ca–vinyl are increased in the order of Oa (2.89–2.92 Å) < Ca (3.13–3.17 Å) < Sa (3.23–3.24 Å), which are related with the vdW radii of the Xa atoms. Hence, the two stacked fragments in ii- and oo-conformers possess good symmetries, but each of two fragments in io conformers locate in asymmetric manners. To study conformational behavior of these TPE-cored foldamers, the thermal corrected Gibbs free energies are calculated and listed in Supporting Information Table S2. The results reveal that three kinds of conformations for each foldamer are almost isoenergetic with small energy differences ≤ 0.95 kcal mol−1, illuminating the thermodynamic coexistence of all of three conformers for each foldamer. But remarkably, the energies of f-TPE-[2]BFu and f-TPE-[2]BTh are ∼6.5 and ∼3.0 kcal mol−1 lower than those of their isomers, f-TPE-[5]BFu and f-TPE-[5]BTh, respectively, indicating the better stability of the former two with a benzene–heterocycle stacking model. What is more, taking f-TPE-[2]BTh (Figure 2), f-TPE-Th, f-TPE-PTh, and f-TPE-[5]BTh ( S

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom.

This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin(benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020.

Site-Selective Silver-Catalyzed C-H Bond Deuteration of Five-Membered Aromatic Heterocycles and Pharmaceuticals.

Catalytic methods for the direct introduction of hydrogen isotopes into organic molecules are essential to the development of improved pharmaceuticals and to the alteration of their absorption, distribution, metabolism, and excretion (ADME) properties. However, the development of homogeneous catalysts for selective incorporation of isotopes in the absence of directing groups under practical conditions remains a long-standing challenge. Here, we show that a phosphine-ligated, silver-carbonate complex catalyzes the site-selective deuteration of C-H bonds in five-membered aromatic heterocycles and active pharmaceutical ingredients that have been resistant to catalytic H/D exchange. The reactions occur with CH3OD as a low-cost source of the isotope. The silver catalysts react with five-membered heteroarenes lacking directing groups, tolerate a wide range of functional groups, and react in both polar and nonpolar solvents. Mechanistic experiments, including deuterium kinetic isotope effects, determination of kinetic orders, and identification of the catalyst resting state, support C-H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-determining step of the catalytic cycle.

Fused Heterocyclic Molecule-Functionalized N-Doped Reduced Graphene Oxide by Non-Covalent Bonds for High-Performance Supercapacitors.

Indole molecules with fused heteroaromatic structures can be adsorbed on the N-doped graphene surface through the π-π interaction. Therefore, the indole-functionalized N-doped graphene (InFGN) with mesopores is successfully fabricated by a simple hydrothermal method and subsequent vacuum freeze-drying process. The microstructure, thickness, element composition, pore structure, and electrochemical performance of InFGN are analyzed via SEM, TEM, AFM, BET, UV-vis, FT-IR, XPS, Raman, XRD, and electrochemical technologies. Since the five-membered aromatic heterocycles are electron-rich, the indole molecules fixed on the N-doped graphene surface can repair the structural defects generated by N doping. Electrochemical measurements show that the InFGN electrode highlights an excellent capacitance of 622.3 F g-1 at 2 A g-1 and a durable cycling life of 100.5% after 5000 charging/discharging cycle times. For further practical application, a symmetric device has been assembled by using InFGN electrodes, which realizes high-power and energy densities (18.8-20.6 Wh kg-1 at 800-8000 W kg-1). This study provides a shortcut for building green supercapacitors with enhanced energy storage performance.

Tandem Catalysis: Synthesis of Nitrogen-Containing Heterocycles

In this Review, we consider all the publications since the beginning of the century that describe tandem reactions resulting in the formation of five-membered aromatic nitrogen heterocycles (thiazole, imidazole, indole, tetrazole, triazole, and isoxazole). The contents of this review are organized by taxonomy and type of tandem catalysis. It covers orthogonal, auto-, and assisted tandem catalysis, providing an overview of tandem reactions applied tonitrogen heterocycles reported in the literature up to March 2020. We believe that this compilation of data will provide a necessary starting reference to developthe applications of tandem catalysis in medicinal chemistry.

Synthesis, Optical and Electrochemical Properties of D1–A–D2–A–D1 Type Conjugated Donor-Acceptor Assemblies of Five-Membered Aromatic Heterocycles

Novel conjugated systems of the D1–A–D2–A–D1 type were synthesized based on 3.3”-decyl[2.2':5',2”-terthiophene]-5.5”- and 3.3”'-didecyl[2.2':5',2”:5”,2”'-quaterthiophene]-5.5”'-dicarboxylic acids. In obtained systems, two electron-withdrawing heterocycles 1,3,4-thiadiazole or 1,3,4-oxadiazole are separated by alkyl-substituted thiophene units. The optical and electrochemical properties of all the synthesized structures were studied. The influence of the structure of the synthesized compounds on the band gap and the position of the boundary orbitals was established.

Recent Progress in the Synthesis of Furan

Furans are five-membered aromatic heterocycles containing one oxygen atom that are important building blocks in organic chemistry, but also as natural products found in various natural sources, mostly in plants, algae and microorganisms. In this review, we discussed recent advances in the synthesis of furan compounds. Some classical methods have been modified and improved, while other new methods have been developed. A vast variety of catalysts was used for these transformations. In many studies, furan synthesis reaction mechanisms were also investigated and proposed.

Graphene hydrogels functionalized non-covalently by fused heteroaromatic molecule for asymmetric supercapacitor with ultra-long cycle life

A redox-active organic molecular electrode is prepared for supercapacitors. Benzo[1,2-b:4,5-b']dithiophene-4,8-dione (BDTD), planar molecule with fused heteroaromatic structure, has been adsorbed on conductive reduced graphene oxide (rGO) by π–π interactions to form a 3D interconnected and functionalized xerogel (BDTD-rGO). Because the five-membered aromatic heterocycle is more electron-rich than the six-membered aromatic ring, which enlarges the electronic interaction between the BDTD molecule and the conjugated graphene network and accordingly reduce the solubility of BDTD molecule in electrolyte. As a result, the optimized BDTD-rGO electrodes achieve specific capacitance of 360 F g−1 at 1 A g−1, with ultra-long cycle life of 96.4% after 10,000 cycles, and even 80% after 50,000 cycles at 5 A g−1 in 1 M H2SO4. Furthermore, the asymmetric supercapacitor (ASC), which is assembled by using the BDTD-rGO as the negative electrode and lamellar holey graphene hydrogel (LGH) as the positive electrode respectively, exhibits better energy storage performance.

Synthesis of pyrroles via ruthenium-catalyzed nitrogen-transfer [2\u2009+\u20092\u2009+\u20091] cycloaddition of \u03b1,\u03c9-diynes using sulfoximines as nitrene surrogates

Pyrrole is a privileged five-membered aromatic nitrogen heterocycle, which is ubiquitous in natural products, drug molecules, and functional materials. Therefore, numerous synthetic routes to substituted pyrroles have been extensively developed. Nevertheless, the efficient and short-step synthesis of highly substituted and/or fused pyrroles has remained a significant challenge in organic chemistry. Here we report a ruthenium-catalyzed nitrogen-transfer [2 + 2 + 1] cycloaddition of α,ω-diynes involving cyclic biscarbenoid intermediates. To achieve the key nitrogen transfer to carbenoid carbons, sulfoximines are employed as nitrene surrogates. Consequently, diverse fused pyrroles are successfully synthesized in good yields with wide functional group compatibility. Moreover, this method allows the synthesis of N-alkyl, N-aryl, and even N-H pyrroles, which are difficult to obtain using previous [2 + 2 + 1]-type reactions. Nitrogen transfer from sulfoximines to cyclic biscarbenoid intermediates is supported by density functional theory calculations and control experiments.

Lennard-Jones Potentials for the Interaction of CO2 with Five-Membered Aromatic Heterocycles.

We used M06-2X/Def2-TZVPP to calculate a broad set of rigid interaction profiles between CO2 and 30 different aromatic heterocycles, based on pyrrole, furan, and thiophene with ring positions subsituted with up to four nitrogens. For each system, several orientations of the fragments were explored to both find the preferred interaction mode and have information about other interaction modes that can contribute to the binding energy when CO2 is captured by complex systems. From these data, Lennard-Jones potentials were obtained, which can be used for the parametrization of force fields that correctly describe the multipolar and dispersion interactions at play between these kinds of fragments. These results are expected to contribute to the development of new force fields for the study of chemical systems for the capture and sequestration of CO2 and also directly for the design of such systems.

CO2 Complexes with Five-Membered Heterocycles: Structure, Topology, and Spectroscopic Characterization.

In a first step toward the rational design of macrocyclic structures optimized for CO2 capture, we systematically explored the potential of 30 five-membered aromatic heterocycles to establish coordinating complexes with this pollutant. The interactions between the two moieties were studied in several orientations, and the obtained complexes were analyzed in terms of electron density and vibrational fingerprint. The former is an aid to provide an in-depth knowledge of the interaction, whereas the latter should help to select structural motifs that have not only good complexation properties but also diagnostic spectroscopic signals.

Recent Advances in the Synthesis of Benzimidazole Derivatives from the Oxidative Coupling of Primary Amines

Benzimidazole belongs to the top five most commonly used five-membered aromatic nitrogen heterocycles among U.S. FDA approved pharmaceuticals. Over the last few years, a large number of improved synthetic strategies have been developed to construct the benz­imidazole molecular framework under environmentally benign conditions. This review focuses on the use of primary amines as readily available substrates for the synthesis of benzimidazole derivatives through different types of oxidative cross-coupling reactions.1 Introduction2 Catalyst-Free Oxidative Coupling of Primary Amines3 Catalytic Oxidative Coupling of Primary Amines3.1 Metal-Catalyzed Reactions3.2 Metal-Free Catalyzed Reactions3.3 Bioinspired Catalyzed Reactions4 Conclusion