Bibenzyl and naphthalene derivatives from Dendrobium chrysanthum and their anti-hepatic-steatosis activities.

In this study, 16 new compounds, six bibenzyls (1-6) and 10 naphthalenes (7-13), including three pairs of naphthalene enantiomers and three known compounds (14-16), were isolated from Dendrobium chrysanthum. Structurally, compounds 1-5 are previously undescribed dimeric bibenzyls, uniquely linked by unusual carbon bonds. The structures of the compounds were determined using spectroscopy and X-ray crystallography. The screening results indicated that 1, 2, and 5 showed remarkable lipid-lowering activities in FFA-induced HepG2 cells, with EC50 values ranging from 3.13 to 6.57 µM. Moreover, 1, 2, and 5 significantly decreased both the mRNA and protein levels of the target SREBP-1c, and 5 also reduced PPARα mRNA and protein levels. Therefore, 1, 2, and 5 are potential drugs against hepatic steatosis by targeting PPARα or SREBP-1c.

Unraveling the atmospheric oxidation mechanism and kinetics of naphthalene: Insights from theoretical exploration.

Naphthalene, the most abundant polycyclic aromatic hydrocarbon in the atmosphere, significantly influences OH consumption and secondary organic aerosol (SOA) formation. Naphthoquinone (NQ) is a significant contributor to ring-retaining SOA from naphthalene degradation, impacting the redox properties and toxicity of ambient particles. However, inconsistencies persist regarding concentrations of its isomers, 1,2-NQ and 1,4-NQ. In present work, our theoretical investigation into naphthalene's reaction with OH and subsequent oxygenation unveils their role in SOA formation. The reaction kinetics of initial OH and subsequent O2 oxidation was extensively studied using high-level quantum chemical methods (DLPNO-CCSD(T)/aug-ccpVQZ//M052x-D3/6-311++G(d,p)) combined with RRKM/master equation simulations. The reactions mainly proceed through electrophilic addition and abstraction from the aromatic ring. The total rate coefficient of naphthalene + OH at 300 K and 1 atm from our calculation (7.2 × 10-12 cm3 molecule-1 s-1) agrees well with previous measurements (∼1 × 10-11 cm3 molecule-1 s-1). The computed branching ratios facilitate accurate product yield determination. The largest yield of 1-hydroxynaphthalen-1-yl radical (add1) producing the major precursor of RO2 is computed to be 93.8 % in the ambient environment. Our calculated total rate coefficient (5.2 × 10-16 cm3 molecule-1 s-1) for add1 + O2 closely matches that of limited experimental data (8.0 × 10-16 cm3 molecule-1 s-1). Peroxy radicals (RO2) generated from add1 + O2 include 4-cis/trans-(1-hydroxynaphthalen-1-yl)-peroxy radical (add1-4OOadd-cis/trans, 66.0 %/17.5 %), 2-cis/trans-(1-hydroxynaphthalen-1-yl)-peroxy radical (add1-2OOadd-cis/trans, 10.3 %/6.3 %). Regarding the debated predominance of 1,4-NQ (corresponding to the parent RO2, i.e., add1-4OOadd-cis/trans) and 1,2-NQ (corresponding to the parent RO2, i.e., add1-2OOadd-cis/trans) in the atmosphere, our findings substantiate the dominance of 1,4-NQ. This study also indicates potential weakening of 1,4-NQ's dominance due to competition from decomposition reactions of add1-4OOadd-cis/trans and add1-2OOadd-cis/trans. Precise reaction kinetics data are essential for characterizing SOA transformation derived from naphthalene and assessing their climatic impacts within modeling frameworks.

Naphthalene Diimide-Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action.

Human immunodeficiency virus 1 (HIV-1) therapeutic regimens consist of three or more drugs targeting different steps of the viral life cycle to limit the emergence of viral resistance. In line with the multitargeting strategy, here we conjugated a naphthalene diimide (NDI) moiety with a tetraazacycloalkane to obtain novel naphthalene diimide (NDI)-tetraazacycloalkane conjugates. The NDI inhibits the HIV-1 promoter activity by binding to LTR G-quadruplexes, and the tetraazacycloalkane mimics AMD3100, which blocks HIV entry into cells by interfering with the CXCR4 coreceptor. We synthesized, purified, and tested the metal-free NDI-tetraazacycloalkane conjugate and the two derived metal-organic complexes (MOCs) that incorporate Cu2+ and Zn2+. The NDI-MOCs showed enhanced binding to LTR G4s as assessed by FRET and CD assays in vitro. They also showed enhanced activity in cells where they dose-dependently reduced LTR promoter activity and inhibited viral entry only of the HIV-1 strain that exploited the CXCR4 coreceptor. The time of addition assay confirmed the dual targeting at the different HIV-1 steps. Our results indicate that the NDI-MOC conjugates can simultaneously inhibit viral entry, by targeting the CXCR4 coreceptor, and LTR promoter activity, by stabilizing the LTR G-quadruplexes. The approach of combining multiple targets in a single compound may streamline treatment regimens and improve the overall patient outcomes.

Influence of structural characteristics on the binding of synthetic cannabinoids from the JWH family to the CB1 receptor: A computational study.

Synthetic cannabinoids, including some from the John W. Huffman (JWH) family, emerged on the drug scene around 2004 as "alternative marijuana," despite being considerably more potent than marijuana. Like Δ9-tetrahydrocannabinol (THC), the principal psychoactive ingredient in marijuana, synthetic cannabinoids have also been found to interact with cannabinoid receptors CB1 and CB2, found in the brain, immune system, and peripheral organs. The JWH compounds and other synthetic cannabinoids have become important subjects of research in the forensic science community due to their drug-abuse potential, undetectability under routine drug screening, and unpredictable toxicity. In this study, an active-state CB1 receptor model was used to assess the receptor-ligand interactions between the CB1 receptor and ligands from the JWH synthetic cannabinoid family, as well as some newly designed JWH-like virtual compounds, labeled as MGCS compounds, using docking, binding free-energy calculations (ΔG), and molecular dynamics simulations (MDs). The calculated ΔG revealed that the carbonyl group between the naphthalene and the indole, characteristic of the JWH family, and the length of the N-linked alkyl chain were two important structural characteristics that influenced the predicted CB1 binding affinity, especially as increasing the length of the alkyl chain led to better predicted binding affinity. MDs and per-residue-breakdown results showed that the designed MGCS compounds with a pentyl chain attached to the naphthalene moiety and selected JWH compounds formed stable and strong hydrophobic interactions with the key residues Phe170, Phe174, Phe177, Phe200, Phe268, and Trp279 of the CB1 receptor. Comprehension of these critical interactions can help forensic chemists predict the structure of undiscovered families of synthetic cannabinoids.

Structural modification of C2-substituents on 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acid derivatives as potent inhibitors of the Keap1-Nrf2 protein-protein interaction.

The Keap1-Nrf2-ARE signaling pathway is an attractive therapeutic target for the prevention and treatment of oxidative stress-associated diseases by activating the cellular expression of cytoprotective enzymes and proteins. Small molecule inhibitors can directly disrupt the Keap1-Nrf2 protein-protein interaction (PPI), resulting in elevated levels of Nrf2 protein and subsequent stimulation of related antioxidant responses. Previously, we found that 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acid derivatives with an ether type C2-substituent on the benzene or naphthalene core exhibited potent inhibitory activities with IC50's in the submicromolar or nanomolar range. We here describe a more detailed structure-activity relationship study around the C2 substituents containing various polar linkers shedding new insight on their binding interactions with the Keap1 Kelch domain. The key observation from our findings is that the substituents at the C2-position of the benzene or naphthalene scaffold impact their inhibitory potencies in biochemical assays as well as activities in cell culture. The biochemical FP and TR-FRET assays revealed that the naphthalene derivatives 17b and 18 with an additional carboxylate at the C2 were the most active inhibitors against Keap1-Nrf2 PPI. In the cell-based assay, the two compounds were shown to be potent Nrf2 activators of the transcription of the Nrf2-dependent genes, such as HMOX2, GSTM3, and NQO1.

The Influence of Chirality on the ß-Amino-Acid Naphthalenediimides/G-Quadruplex DNA Interaction.

G-quadruplexes (G4s) have been identified as a potential alternative chemotherapy target. A series of eight ß-amino acid derived naphthalenediimides (NDI) were screened against a series of oncogenic G4 sequences: c-KIT1, h-TELO, and TBA. Three sets of enantiomers were investigated to further our understanding of the effect of point chirality on G4 stabilisation. Enantioselective binding behaviour was observed with both c-KIT1 and h-TELO. Docking studies using GNINA and UV-vis titrations were employed to better understand this selective binding behaviour.

Hierarchical assembly of foldable polymers and applications in organic optoelectronics and antibacterial or antiviral materials.

Aggregation of amphiphilic polymers in block-selective solvents produces different nanostructures, which have been studied extensively for wide-ranging applications. Nevertheless, such immiscibility-driven aggregation does not endow them with the desired structural precision, predictability or surface functional group exposure, which significantly impact their functional applications. More recently, biomimetic folded structures of synthetic macromolecules (mostly oligomers) have come to the fore, but such studies have been limited to probe the secondary structures. In this article, we have collated hierarchical structures of foldamers, especially highlighting our recent contribution to the field of chain-folding regulated assembly of segmented polyurethanes (PUs) and their functional applications. A series of such PUs have been discussed, which contain a segmented hydrocarbon backbone and alternately placed pendant solvophilic groups. In either water or highly non-polar solvents (TCE, MCH), depending on the nature of the pendant group, they exhibit folded structures stabilized by intra-chain H-bonding. Hierarchical assembly of such folded chains by inter-chain H-bonding and/or π-stacking leads to the formation of well-defined nanostructures with functional applications ranging from organic optoelectronics to biomaterials. For example, a segmented PU with appended naphthalene-diimide (NDI) chromophores showed a pleated structure in MCH, which helped in organization of the NDI chromophores within π-stacking distance. Such folded polymer chains eventually produced nanotubular structures with excellent electron mobility. They also showed efficient intercalation of the pyrene (Py) donor by NDI-Py charge-transfer interaction and in this case the mixed nanotubular structure exhibited prominent room-temperature ferroelectricity. On the other hand, having cationic functionalities as the pendant groups such chain-folding regulated assembly produced unilamellar polymersomes with excellent antibacterial activity with very low minimum inhibitory concentrations (<10 µg mL-1). Replacing the pendant amine functionality with sulphate groups made these polyurethanes highly potent antiviral materials. In the absence of the alternating connectivity of the solvophobic and solvophilic segments or rigid hydrocarbon backbone, such folding propensity is destroyed, leading to structural collapse. While significant efforts have been made in correlating primary structures of wide-ranging polymers with their functional applications, this article demonstrates the direct correlation between the secondary structures of polymers and their functional properties.

Quantifying Amide-Aromatic Interactions at Molecular and Atomic Levels: Experimentally Determined Enthalpic and Entropic Contributions to Interactions of Amide sp2O, N, C and sp3C Unified Atoms with Naphthalene sp2C Atoms in Water.

In addition to amide hydrogen bonds and the hydrophobic effect, interactions involving π-bonded sp2 atoms of amides, aromatics, and other groups occur in protein self-assembly processes including folding, oligomerization, and condensate formation. These interactions also occur in aqueous solutions of amide and aromatic compounds, where they can be quantified. Previous analysis of thermodynamic coefficients quantifying net-favorable interactions of amide compounds with other amides and aromatics revealed that interactions of amide sp2O with amide sp2N unified atoms (presumably C═O···H-N hydrogen bonds) and amide/aromatic sp2C (lone pair π, n-π*) are particularly favorable. Sp3C-sp3C (hydrophobic), sp3C-sp2C (hydrophobic, CH-π), sp2C-sp2C (hydrophobic, π-π), and sp3C-sp2N interactions are favorable, sp2C-sp2N interactions are neutral, while sp2O-sp2O and sp2N-sp2N self-interactions and sp2O-sp3C interactions are unfavorable. Here, from determinations of favorable effects of 14 amides on naphthalene solubility at 10, 25, and 45 °C, we dissect amide-aromatic interaction free energies into enthalpic and entropic contributions and find these vary systematically with amide composition. Analysis of these results yields enthalpic and entropic contributions to intrinsic strengths of interactions of amide sp2O, sp2N, sp2C, and sp3C unified atoms with aromatic sp2C atoms. For each interaction, enthalpic and entropic contributions have the same sign and are much larger in magnitude than the interaction free energy itself. The amide sp2O-aromatic sp2C interaction is enthalpy-driven and entropically unfavorable, consistent with direct chemical interaction (e.g., lone pair-π), while amide sp3C- and sp2C-aromatic sp2C interactions are entropy-driven and enthalpically unfavorable, consistent with hydrophobic effects. These findings are relevant for interactions involving π-bonded sp2 atoms in protein processes.

Chalcogen-bridged coordination polymer for the photocatalytic activation of aryl halides.

The ability to deliver electrons is vital for dye-based photocatalysts. Conventionally, the aromatic stacking-based charge-transfer complex increases photogenerated electron accessibility but decreases the energy of excited-state dyes. To circumvent this dilemma, here we show a strategy by tuning the stacking mode of dyes. By decorating naphthalene diimide with S-bearing branches, the S···S contact-linked naphthalene diimide string is created in coordination polymer, thereby enhancing electron mobility while simultaneously preserving competent excited-state reducing power. This benefit, along with in situ assembly between naphthalene diimide strings and exogenous reagent/reactant, improves the accessibility of short-lived excited states during consecutive photon excitation, resulting in greater efficiency in photoinduced electron-transfer activation of inert bonds in comparison to other coordination polymers with different dye-stacking modes. This heterogeneous approach is successfully applied in the photoreduction of inert aryl halides and the successive formation of CAr-C/S/P/B bonds with potential pharmaceutical applications.

Multicomponent All-Carbon Cascade and Sequential Annulation: Construction of Functionalized Decalins.

The decalin skeleton is found in numerous bioactive molecules. The present study describes a multicomponent all-carbon cascade and sequential annulation involving benzoylacetonitrile derivatives and 2-arylidene-1,3-indanediones that yields highly functionalized decalin derivatives. The reaction strategy consisted of a consecutive Michael/Michael/tautomerization/Michael/Aldol annulation sequence and involved organic amine catalysts, mild conditions, and high stereoselectivity. This strategy, using a one-pot approach, resulted in the construction of four C-C bonds and the formation of fused carbocyclic decalin derivatives.

Wakodecaline C, new tetrahydrofuran-fused decalin metabolite isolated from fungus Pyrenochaetopsis sp. RK10-F058.

A new decalin-containing secondary metabolite, wakodecaline C, was isolated from a fungus Pyrenochaetopsis sp. RK10-F058 by screening structurally interesting metabolites based on LC/MS profiling. The structure including the absolute configuration was determined by a combination of spectroscopic methods including NMR and mass spectrometry, chemical reaction, and calculation of ECD spectra. Wakodecaline C has unique structural features containing a tetrahydrofuran-fused decalin skeleton and tetramic acid moiety, which are connected through a double bond. The compound showed moderate cytotoxicity against HL-60 cells and antimalarial activity against the Plasmodium falciparum 3D7 strain.

Supramolecular Recognition of Phosphodiester-Based Donor and Acceptor Oligomers Forming Gels in Water.

Inspired by automated DNA synthesis, electron-rich dialkoxynaphthalene (DAN) donor and electron-deficient naphthalene-tetracarboxylic diimide (NDI) acceptor phosphodiester-linked homohexamers were synthesized by the phosphoramidite method. Two types of hexamers were prepared, one with only one phosphodiester between the aromatics (i.e., DAN or NDI) and a second with two phosphodiesters around a propanediol between the aromatics, leading to the latter more flexible and more hydrophilic hexamers. The folding properties of these homohexamers alone or mixed together, in water only, were studied by UV-visible absorption spectroscopy and atomic force microscopy (AFM). AFM imaging revealed that a 1:1 mixture of hexaDAN and hexaNDI formed fibers by charge transfer donor-acceptor recognition leading to a hydrogel after drying. The organization of the resulting structures is strongly dependent on the nature of the complementary partner, leading to the formation of mono- or multilayer hydrogel networks with different compactness.

Monitoring the Light-induced Isomerisation of the Prototypical Polycyclic Aromatic Hydrocarbons C10 H8 + through Ion-Molecule Reactions.

Structural rearrangements in ions are essential for understanding the composition and evolution of energetic and chemically active environments. This study explores the interconversion routes for simple polycyclic aromatic hydrocarbons, namely naphthalene and azulene radical cations (C10 H8 + ), by combining mass spectrometry and vacuum ultraviolet tunable synchrotron radiation through the chemical monitoring technique. Products of ion-molecule reactions are used to probe C10 H8 + structures that are formed as a function of their internal energies. Isomerisation from azulene radical cation towards naphthalene radical cation in a timescale faster than 80 µs was monitored, whereas no reverse isomerisation was observed in the same time window. When energising C10 H8 + with more than 6 eV, the reactivity of C10 H8 + unveils the formation of a new isomeric group with a contrasted reactivity compared with naphthalene and azulene cations. We tentatively assigned these structures to phenylvinylacetylene cations.

Iontophoresis application for drug delivery in high resistivity membranes: nails and teeth.

Iontophoresis has been vastly explored to improve drug permeation, mainly for transdermal delivery. Despite the skin's electrical resistance and barrier properties, it has a relatively high aqueous content and is permeable to many drugs. In contrast, nails and teeth are accessible structures for target drug delivery but possess low water content compared to the skin and impose significant barriers to drug permeation. Common diseases of these sites, such as nail onychomycosis and endodontic microbial infections that reach inaccessible regions for mechanical removal, often depend on time-consuming and ineffective treatments relying on drug's passive permeation. Iontophoresis application in nail and teeth structures may be a safe and effective way to improve drug transport across the nail and drug distribution through dental structures, making treatments more effective and comfortable for patients. Here, we provide an overview of iontophoresis applications in these "hard tissues," considering specificities such as their high electrical resistivity. Iontophoresis presents a promising option to enhance drug permeation through the nail and dental tissues, and further developments in these areas could lead to widespread clinical use.

Adsorption of naphthalene and its derivatives onto high-density polyethylene microplastic: Computational, isotherm, thermodynamic, and kinetic study.

Microplastics (MP) have received great attention due to the mass-produced residues discharged into the environment. MP are ideal for adhering to organic pollutants that can be easily dispersed, thus posing risks to human health. Furthermore, little has been reported on how different functional groups in polycyclic aromatic hydrocarbons (PAH) derivatives influence the adsorption behavior on MP. To better understand this process, groups methyl (-CH3) and hydroxyl (-OH) were selected and commercial and waste high-density polyethylene (HDPE, ≤ 1 mm) were used as adsorbents, and Naphthalene (Nap), 1-Methyl-Naphthalene (Me-Nap) and α-Naphthol as adsorbates. The results showed different behaviors for nonpolar and polar adsorbates. Dispersion forces were the main type of interaction between HDPE and Nap/Me-Nap, while dipole-induced dipole forces and H-bonding were the chief interactions involving MP and polar compounds. Regardless the HDPE source, Nap and Me-Nap have a Type III isotherm, and α-Naphthol presents a Type II isotherm. Nap and Me-Nap fitted to Freundlich isotherm of an unfavorable process (n = 2.12 and 1.11; 1.87 and 1.31, respectively), with positive values of ΔH° (50 and 77.17; 66 and 64.63 kJ mol-1) and ΔS° (0.070 and 0.0145; 0.122 and 0.103 kJ mol-1) for commercial and waste MP, respectively. Besides, the adsorption isotherm of α-Naphthol on commercial and waste HDPE fitted to the Langmuir model (Qmax = 42.5 and 27.2 µmol g-1, respectively), presenting negative values of ΔH° (-43.71 and -44.10 kJ mol-1) and ΔS° (-0.037 and -0.025 kJ mol-1). The adsorption kinetic study presents a nonlinear pseudo-second-order model for all cases. The K2 values follow the order Me-Nap > Nap > α-Naphthol in both MP. Therefore, this experimental study provides new insights into the affinity of PAH derivatives for a specific class of MP, helping to understand the environmental fate of residual MP and organic pollutants.

Design, Synthesis and Biological Evaluation of Syn and Anti-like Double Warhead Quinolinones Bearing Dihydroxy Naphthalene Moiety as Epidermal Growth Factor Receptor Inhibitors with Potential Apoptotic Antiproliferative Action.

Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a−e and 7a−e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a−e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal−Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a−e and 7a−e were evaluated. Compounds 4a−e and 7a−e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids.

Impact of the Hydrogen-Bonding Functional Group on Hydrogelation of Amphiphilic Naphthalene-diimide Derivatives and Nonspecific Protein Adsorption.

This manuscript reports the effect of hydrogen-bonding functionality on the supramolecular assembly of naphthalene-diimide (NDI)-derived amphiphilic building blocks in water. All the molecules contain a central NDI chromophore, functionalized with a hydrophilic oligo-oxyethylene (OE) wedge in one arm and a phenyl group on the opposite arm. They differ by a single H-bonding functionality, which links the NDI chromophore and the phenyl moiety. The H-bonding functionalities are amide, thioamide, urea, and urethane in NDI-A, NDI-TA, NDI-U, and NDI-UT, respectively. All of these molecules exhibit π-stacking in water, as evident from their distinct UV/vis absorption spectra when compared to that of the monomeric dye in THF. However, among these four, only NDI-A and NDI-TA show hydrogelation, while the other two precipitate out of the medium. The NDI-A hydrogel also exhibits transient stability and leads to a crystalline precipitate within ∼5 h. Only NDI-TA produces stable transparent hydrogel with the entangled fibrillar morphology that is typical for gelators. Both NDI-A and NDI-TA showed a thermoresponsive property with a lower critical solution temperature of about 41-42 °C. Powder XRD studies show a parallel orientation for NDI-A and an antiparallel orientation for NDI-TA. Computational studies support this experimental observation and indicate that the NDI-A assembly is highly stabilized by strong H-bonding among the amide groups and π-stacking interaction in the parallel orientation. On the other hand, due to weak H-bonding among the thioamide groups, the binding energy of the parallelly oriented NDI-TA was significantly lower and the optimized structure was disordered. Instead, its antiparallel orientation was more stable, with criss-cross aligned H-bonding interactions and π-π interactions between adjacent aromatic rings. The NDI-TA hydrogel with less ordered OE chains on the surface showed prominent adsorption of serum protein BSA. In sharp contrast, NDI-A did not exhibit any notable interaction with BSA, as evident from the ITC studies.

Phosphorous NMR Analysis and Activity of Chiral BINAP-Silver Complexes.

Chiral Ag-atropisomeric ligand species were studied in solution at different temperatures by 31 P-NMR spectroscopy. The analysis and understanding of key parameters in Ag-BINAP complexes were considered in the context of an enantioselective transformation. An efficient silver-catalyzed intramolecular [4+2] cycloaddition reaction of amide-1,6-enyne provided an enantiomerically enriched tricyclic compound using simple reagents and under mild reaction conditions.

Understanding the Nature and Strength of Noncovalent Face-to-Face Arene-Fullerene Interactions.

Face-to-face noncovalent arene-fullerene interactions are important in several research fields such as synthetic chemistry, materials chemistry, and medicinal chemistry; however, their nature and strength are still poorly understood. In this study, we prepare a fullerene-based torsion balance containing thioanisole, phenol, naphthalene, azulene, and pyrene moieties as a unimolecular model system. Moreover, we compare the folding free energies between the folded and the unfolded conformers of a series of the molecular torsion balances to quantify noncovalent interactions between arenes and the fullerene surface. This work demonstrates that the contributions of polarizabilities, anionic charges, electronic dipole moments, and the number of arene rings to the interactions can be experimentally measured by analyzing the folding equilibrium of the molecular torsion balances.

Organocatalytic Enantioselective Synthesis of Axially Chiral Molecules: Development of Strategies and Skeletons.

The growing importance of axially chiral architectures in different scientific domains has unveiled shortcomings in terms of efficient synthetic access and skeletal variety. This account describes our strategies in answering these challenges within the organocatalytic context where the emergence of bifunctional catalysts such as chiral phosphoric acids (CPAs) has proven invaluable in controlling the sense of axial chirality. The wide occurrence of bi(hetero)aryl skeletons in privileged structures constitutes a strong motivation to devise more effective arylation methods. Our design revolves around modulating the intrinsic nucleophilicity of aromatic amines and alcohols. The first approach involves the design of an electron-withdrawing activating group which could associate with the catalyst for reactivity enhancement and selectivity control. The resonance of arenes offers the unique mechanistic possibility to select between activating sites. C2-Azo- and nitroso-substituted naphthalenes undergo atroposelective ortho C- or N-arylation with (hetero)aromatic nucleophiles. For monocyclic benzenes, programmable charge localization leads to regioselective activation by catalytic control alone or aided by substrate design. For instance, selective addition to nitroso nitrogen enables successive annulation initiated by the amine to yield axially chiral N-arylbenzimidazoles. In a biomimetic manner, a finely tuned catalyst could direct a para-selective nucleophilic approach in the atroposelective arylation of azobenzenes. The second strategy employs electrophilic arene precursors for arylation which occurs via rearomatization with central-to-axial chirality transfer. This enabled the arylation of (imino)quinones with indoles to access phenylindole atropisomers. By adapting this chemistry with an additional oxidation event to liberate the carbonyl functionalities, aryl-o-naphthoquinone and aryl-p-quinone atropisomers were attained. Along with the development of new arylation strategies, deriving new axially chiral structures has been another consistent theme of our research program. The atroposelective functionalization of alkynes provides broad entry to atropisomeric alkenes. The monofunctionalization of alkynes through the interception of an electrophilic vinylidene-quinone-methide (VQM) intermediate with 2-naphthols yielded the new EBINOL scaffolds. By designing an internal directing group, the atroposelective dihalogenation of alkynes was realized using abundant alkali halides despite their weak nucleophilicities and poor solubilities. The atroposelective N-alkylation of alkenes was pursued to prepare multifunctionalized alkene atropisomers that could be converted into 2-arylpyrroles with chirality transfer. The synthesis of B-aryl-1,2-azaborines containing a C-B chiral axis was accomplished where the CPA catalyst effects the desymmetrization and defines the configuration of the distal C-B bond. Inspired by the axially chiral scaffold of allenes, we leveraged the developed arene activation strategy to achieve para-addition and dearomatization of judiciously designed azobenzenes, which led to structurally novel cyclohexadienylidene-based hydrazones. To complement these structures, axially chiral cyclohexadienyl oxime ethers were also attained through CPA-catalyzed condensation between hydroxylamines and spiro[4.5]trienones.