Structural characterization of the supra-molecular complex between a tetra-quinoxaline-based cavitand and benzo-nitrile.

The structural characterization is reported of the supra-molecular complex between the tetra-quinoxaline-based cavitand 2,8,14,20-tetra-hexyl-6,10:12,16:18,22:24,4-O,O'-tetra-kis-(quinoxaline-2,3-di-yl)calix[4]resorcinarene (QxCav) with benzo-nitrile. The complex, of general formula C84H80N8O8·2C7H5N, crystallizes in the space group P with two independent mol-ecules in the asymmetric unit, displaying very similar geometrical parameters. For each complex, one of the benzo-nitrile mol-ecules is engulfed inside the cavity, while the other is located among the alkyl legs at the lower rim. The host and the guests mainly inter-act through weak C-H⋯π, C-H⋯N and dispersion inter-actions. These inter-actions help to consolidate the formation of supra-molecular chains running along the crystallographic b-axis direction.

Membranes with Molecular Gatekeepers for Efficient CO2 Capture and H2 Purification.

The urgent need for CO2 capture and hydrogen energy has attracted great attention owing to greenhouse gas emissions and global warming problems. Efficient CO2 capture and H2 purification with membrane technology will reduce greenhouse gas emissions and help reach a carbon-neutral society. Here, 4-sulfocalix[4]arene (SC), which has an intrinsic cavity, was embedded into the Matrimid membrane as a molecular gatekeeper for CO2 capture and H2 purification. The interactions between SC and the Matrimid polymer chains immobilize SC molecules into the interchain gaps of the Matrimid membrane, and the strong hydrogen and ionic bondings were able to form homogeneous mixed-matrix membranes. The incorporation of the SC molecular gatekeeper with exceptional molecular-sieving properties improved the gas separation performance of the mixed-matrix membranes. Compared with that of the Matrimid membrane, the CO2 permeability of the Matrimid-SC-3% membrane increased from 16.75 to 119.78 Barrer, the CO2/N2 selectivity increased from 29.39 to 106.95, and the CO2/CH4 selectivity increased from 29.91 to 140.92. Furthermore, when the permeability of H2 was increased to 172.20 Barrer, the H2/N2 and H2/CH4 selectivities reached approximately 153.75 and 202.59, respectively, which are far superior to those of most existing Matrimid-based materials. The mixed-matrix membranes also exhibited excellent long-term operation stability, with separation performance for several important gas pairs still overtaking the Robeson upper limit after aging for 400 days.

Dynamic and Assembly Characteristics of Deep-Cavity Basket Acting as a Host for Inclusion Complexation of Mitoxantrone in Biotic and Abiotic Systems.

We describe the preparation, dynamic, assembly characteristics of vase-shaped basket 13- along with its ability to form an inclusion complex with anticancer drug mitoxantrone in abiotic and biotic systems. This novel cavitand has a deep nonpolar pocket consisting of three naphthalimide sides fused to a bicyclic platform at the bottom while carrying polar glycines at the top. The results of 1 H Nuclear Magnetic Resonance (NMR), 1 H NMR Chemical Exchange Saturation Transfer (CEST), Calorimetry, Hybrid Replica Exchange Molecular Dynamics (REMD), and Microcrystal Electron Diffraction (MicroED) measurements are in line with 1 forming dimer [12 ]6- , to be in equilibrium with monomers 1(R) 3- (relaxed) and 1(S) 3- (squeezed). Through simultaneous line-shape analysis of 1 H NMR data, kinetic and thermodynamic parameters characterizing these equilibria were quantified. Basket 1(R) 3- includes anticancer drug mitoxantrone (MTO2+ ) in its pocket to give stable binary complex [MTO⊂1]- (Kd =2.1 µM) that can be precipitated in vitro with UV light or pH as stimuli. Both in vitro and in vivo studies showed that the basket is nontoxic, while at a higher proportion with respect to MTO it reduced its cytotoxicity in vitro. With well-characterized internal dynamics and dimerization, the ability to include mitoxantrone, and biocompatibility, the stage is set to develop sequestering agents from deep-cavity baskets.

Rapid Access to Chiral and Tripodal Cavitands from ß-Pinene.

We report Pd-catalyzed cyclotrimerization of (+)-α-bromoenone, obtained from monoterpene ß-pinene, into an enantiopure cyclotrimer. This C3 symmetric compound has three bicyclo[3.1.1]heptane rings fused to its central benzene with each ring carrying a carbonyl group. The cyclotrimer undergoes diastereoselective threefold alkynylation with the lithium salts of five terminal alkynes (41-63 %, de=4-83 %). The addition enabled a rapid synthesis of a small library of novel chiral cavitands that, in shape, resemble a tripod stand. These molecular tripods include a tris-bicycloannelated benzene head attached to three alkyne legs twisted in one direction to form a nonpolar cavity with polar groups as feet. Tripods with methylpyridinium and methylisoquinolinium legs, respectively, form inclusion complexes with anti-inflammatory and chiral drugs (R)/(S)-ibuprofen and (R)/(S)-naproxen. The mode of binding shows drug molecules docked in the cavity of the host through ion-ion, cation-π, and C-H-π contacts that, in addition of desolvation, give rise to complexes having millimolar to micromolar stability in water. Our findings open the door to creating a myriad of enantiopure tripods with tunable functions that, in the future, might give novel chemosensors, catalysts or sequestering agents.

Megalo-Cavitands: Synthesis of Acridane[4]arenes and Formation of Large, Deep Cavitands for Selective C70 Uptake.

Deep cavitands, concave molecular containers, represent an important supramolecular host class that has been explored for a variety of applications ranging from sensing, switching, purification and adsorption to catalysis. A major limitation in the field has been the cavitand volume that is restricted by the size of the structural platform utilized (diameter approx. 7 Å). We here report the synthesis of a novel, unprecedentedly large structural platform, named acridane[4]arene (diameter approx. 14 Å), suitable for the construction of cavitands with volumes of up to 814 Å3 . These megalo-cavitands serve as size-selective hosts for fullerenes with mM to sub-µM binding affinity for C60 and C70 . Furthermore, the selective binding of fullerene C70 in the presence of C60 was demonstrated.

Dissipative Formation of Covalent Basket Cages.

Living systems use chemical fuels to transiently assemble functional structures. As a step toward constructing abiotic mimics of such structures, we herein describe dissipative formation of covalent basket cage CBC 5 by reversible imine condensation of cup-shaped aldehyde 2 (i.e., basket) with trivalent aromatic amine 4. This nanosized [4+4] cage (V=5 nm3 , Mw =6150 Da) has shape of a truncated tetrahedron with four baskets at its vertices and four aromatic amines forming the faces. Importantly, tris-aldehyde basket 2 and aliphatic tris-amine 7 undergo condensation to give small [1+1] cage 6. The imine metathesis of 6 and aromatic tris-amine 4 into CBC 5 was optimized to bias the equilibrium favouring 6. Addition of tribromoacetic acid (TBA) as a chemical fuel perturbs this equilibrium to result in the transient formation of CBC 5, with subsequent consumption of TBA via decarboxylation driving the system back to the starting state.

Binding and Assembly of a Benzotriazole Cavitand in Water.

A water-soluble cavitand bearing a benzotriazole upper rim was prepared and characterized. It exists as a dimeric velcraplex in D2 O, but forms host-guest complexes with hydrophobic and amphiphilic guests. Alkanes (C5 to C10), cyclic ketones (C6-C10), cyclic alcohols (C6-C8) and various amphiphilic guests form 1 : 1 cavitand complexes. A cyclic array of hydrogen bonds, bridged by solvent/water (D2 O) molecules, stabilizes the vase conformation of the complexes. With longer alkanes (C12-C15), symmetrical dialkyl amine, urea and phosphate, 2 : 1 host:guest capsules are formed. Computations indicate that additional waters on the upper rim create a self-complementary hydrogen-bonding pattern for capsule formation.

Tunable Supramolecular Cavities Molecularly Homogenized in Polymer Membranes for Ultraefficient Precombustion CO2 Capture.

Processable molecular-sieving membranes are important materials for realizing energy-efficient precombustion CO2 capture during industrial-scale hydrogen production. However, the promising design of mixed matrix membranes (MMMs) that aims to integrate the molecular-sieving properties of nanoporous architectures with industrial processable polymers still faces performance and fabrication issues due to the formation of segregated nanofiller domains in their polymer matrices. Here, an unconventional nanocomposite membrane design is proposed using soluble organic macrocyclic cavitands (OMCs) with tunable open cavity sizes that not only mitigate the formation the discrete nanofiller phases but also deliver distinct molecular-sieving separations. The versatile organic-solvent solubility coupled with highly interactive functionalities of OMCs allows them to obtain molecularly homogeneous mixing with matrix polymers and form only one integral continuous phase crucial to the robust processability of polymers. A series of polybenzimidazole-based molecularly mixed composite membranes (MMCMs) are fabricated via the incorporation of a soluble and thermally stable OMC choice, sulfocalixarenes, with various cavity sizes. These membranes achieve outstanding high-temperature mixed-gas H2 /CO2 separation performances comparable with several state-of-the-art molecular-sieving membranes owing to effective size-sieving gas passages through the open or partially-intruded supramolecular cavities. The broadly tunable structures and functionalities of OMCs would make their MMCMs attractive for other energy-intensive molecular separations.

Reusable Cavitand-Based Electrospun Membranes for the Removal of Polycyclic Aromatic Hydrocarbons from Water.

The removal of toxic and carcinogenic polycyclic aromatic hydrocarbons (PAHs) from water is one of the most intractable environmental problems nowadays, because of their resistance to remediation. This work introduces a highly efficient, regenerable membrane for the removal of PAHs from water, featuring excellent filter performance and pH-driven release, thanks to the integration of a cavitand receptor in electrospun polyacrylonitrile (PAN) fibers. The role of the cavitand receptor is to act as molecular gripper for the uptake/release of PAHs. To this purpose, the deep cavity cavitand BenzoQxCav is designed and synthetized and its molecular structure is elucidated via X-Ray diffraction. The removal efficiency of the new adsorbent material toward the 16 priority PAHs is demonstrated via GC-MS analyses at ng L-1 concentration. A removal efficiency in the 32%, to 99% range is obtained. The regeneration of the membrane is performed by exploiting the pH-driven conformational switching of the cavitand between the vase form, where the PAHs uptake takes place, to the kite one, where the PAHs release occurs. The absorbance and regeneration capability of the membrane are successfully tested in four uptake/release cycles and the morphological stability.

Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation.

The use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin. These cyclodextrin complexes were characterized by nuclear magnetic resonance spectroscopy (NMR). The variations in the 1H-NMR and 13C-NMR chemical shifts allowed to establish the inclusion modes of the compounds into the cyclodextrin cavities, which were supported by docking and molecular dynamics studies. The efficiency of the complexation was quantified by UV-Vis spectrophotometry and spectrofluorimetry, which showed that the protonation equilibria of camptothecin and luotonin A were drastically hampered upon formation of the inclusion complexes. The stabilization of camptothecin towards hydrolysis inside the cyclodextrin cavity was verified by the quantitation of the active lactone form by reverse phase liquid chromatography fluorimetric detection, both in basic conditions and in the presence of serum albumin. The antitumor activity of luotonin A and camptothecin complexes were studied in several cancer cell lines (breast, lung, hepatic carcinoma, ovarian carcinoma and human neuroblastoma) and an enhanced activity was found compared to the free alkaloids, particularly in the case of hydroxypropyl-ß-cyclodextrin derivatives. This result shows that the cyclodextrin inclusion strategy has much potential towards reaching the goal of employing luotonin A or its analogues as stable analogues of camptothecin.

Enantioselective Construction of Modular and Asymmetric Baskets.

The precise positioning of functional groups about the inner space of abiotic hosts is a challenging task and of interest for developing more effective receptors and catalysts akin to those found in nature. To address it, we herein report a synthetic methodology for preparing basket-like cavitands comprised of three different aromatics as side arms with orthogonal esters at the rim for further functionalization. First, enantioenriched A (borochloronorbornene), B (iodobromonorbornene), and C (boronorbornene) building blocks were obtained by stereoselective syntheses. Second, consecutive A-to-B and then AB-to-C Suzuki-Miyaura (SM) couplings were optimized to give enantioenriched ABC cavitand as the principal product. The robust synthetic protocol allowed us to prepare (a) an enantioenriched basket with three benzene sides and each holding either tBu, Et, or Me esters, (b) both enantiomers of a so-called "spiral staircase" basket with benzene, naphthalene, and anthracene groups surrounding the inner space, and (c) a photo-responsive basket bearing one anthracene and two benzene arms.

Supramolecular Control of Singlet Oxygen Generation.

Singlet oxygen (1O2) is the excited state electronic isomer and a reactive form of molecular oxygen, which is most efficiently produced through the photosensitized excitation of ambient triplet oxygen. Photochemical singlet oxygen generation (SOG) has received tremendous attention historically, both for its practical application as well as for the fundamental aspects of its reactivity. Applications of singlet oxygen in medicine, wastewater treatment, microbial disinfection, and synthetic chemistry are the direct results of active past research into this reaction. Such advancements were achieved through design factors focused predominantly on the photosensitizer (PS), whose photoactivity is relegated to self-regulated structure and energetics in ground and excited states. However, the relatively new supramolecular approach of dictating molecular structure through non-bonding interactions has allowed photochemists to render otherwise inactive or less effective PSs as efficient 1O2 generators. This concise and first of its kind review aims to compile progress in SOG research achieved through supramolecular photochemistry in an effort to serve as a reference for future research in this direction. The aim of this review is to highlight the value in the supramolecular photochemistry approach to tapping the unexploited technological potential within this historic reaction.

Comprehensive Characterization of the Self-Folding Cavitand Dynamics.

The conformational equilibria and guest exchange process of a resorcin[4]arene derived self-folding cavitand receptor have been characterized in detail by molecular dynamics simulations (MD) and 1 H EXSY NMR experiments. A multi-timescale strategy for exploring the fluxional behaviour of this system has been constructed, exploiting conventional MD and accelerated MD (aMD) techniques. The use of aMD allows the reconstruction of the folding/unfolding process of the receptor by sampling high-energy barrier processes unattainable by conventional MD simulations. We obtained MD trajectories sampling events occurring at different timescales from ns to s: 1) rearrangement of the directional hydrogen bond seam stabilizing the receptor, 2) folding/unfolding of the structure transiting partially open intermediates, and 3) guest departure from different folding stages. Most remarkably, reweighing of the biased aMD simulations provided kinetic barriers that are in very good agreement with those determined experimentally by 1 H NMR. These results constitute the first comprehensive characterization of the complex dynamic features of cavitand receptors. Our approach emerges as a valuable rational design tool for synthetic host-guest systems.

Enantioselective Alkoxycyclization of 1,6-Enynes with Gold(I)-Cavitands: Total Synthesis of Mafaicheenamine C.

Chiral gold(I)-cavitand complexes have been developed for the enantioselective alkoxycyclization of 1,6-enynes. This enantioselective cyclization has been applied for the first total synthesis of carbazole alkaloid (+)-mafaicheenamine C and its enantiomer, establishing its configuration as R. The cavity effect was also evaluated in the cycloisomerization of dienynes. A combination of experiments and theoretical studies demonstrates that the cavity of the gold(I) complexes forces the enynes to adopt constrained conformations, which results in the high observed regio- and stereoselectivities.

Recent Advances in Halogen Bonded Assemblies with Resorcin[4]arenes.

Resorcinarenes are cavity-containing compounds when in the crown conformation, from the calixarene family of concave compounds. These easy to synthesize macrocycles can be decorated at the upper rim through the eight hydroxyl groups and/or the 2-position of the aromatic ring. They are good synthons in supramolecular chemistry leading to appealing assemblies such as open-inclusion complexes, capsules and tubes through multiple weak interactions with various guests. Halogen bonding (XB) is a highly directional non-covalent interaction by an electron-deficient halogen atom as a donor that interacts with a Lewis base, the XB acceptor. This tutorial review provides an overview of recent advances in halogen-bonded assemblies based on resorcinarenes and their derivatives, specifically focusing on discrete and capsular assemblies.

Stimuli-Responsive Resorcin[4]arene Cavitands: Toward Visible-Light-Activated Molecular Grippers.

Resorcin[4]arene cavitands, equipped with diverse quinone (Q) and [Ru(bpy)2 dppz]2+ (bpy=2,2'-bipyridine, dppz=dipyrido[3,2-a:2',3'-c]phenazine) photosensitizing walls in different configurations, were synthesized. Upon visible-light irradiation at 420 nm, electron transfer from the [Ru(bpy)2 dppz]2+ to the Q generates the semiquinone (SQ) radical anion, triggering a large conformational switching from a flat kite to a vase with a cavity for the encapsulation of small guests, such as cyclohexane and heteroalicyclic derivatives, in CD3 CN. Depending on the molecular design, the SQ radical anion can live for several minutes (≈10 min) and the vase can be generated in a secondary process without need for addition of a sacrificial electron donor to accumulate the SQ state. Switching can also be triggered by other stimuli, such as changes in solvent, host-guest complexation, and chemical and electrochemical processes. This comprehensive investigation benefits the development of stimuli-responsive nanodevices, such as light-activated molecular grippers.

Aromaticity and Chemical Bonding of Chalcogen-Bonded Capsules Featuring Enhanced Magnetic Anisotropy.

We present a theoretical study of chalcogen bonded container capsules (AX +AX ) where X=O, S, Se, and Te, and their encapsulation complexes with n-C9 H20 (n-C9 H20 @AX +AX ). Both Se and Te encapsulation complexes have significant experimental and computed binding energies, analogous to the hydrogen bonded counterparts, while the S and O capsules and their encapsulation complexes show only weak binding energies, which are attributed to different types of bonding: chalcogen S⋅⋅⋅N bonds for S-capsules and π-π stacking and weak hydrogen bonds for the O case. All AX +AX and C9 H20 @AX +AX present unusually high magnetic anisotropies in their interiors. The 1 H NMR spectra of the encapsulation complexes display the proton signals of the encapsulated n-nonane highly upfield shifted, in agreement with the available experimental data for the Se capsule. We found that different factors contribute to the observed magnetic anisotropy of the capsule's interior: for the Te capsule the most important factor is Te's large polarizability; for the O analogue the inductive effects produced by the electronegative nature of the O and N heteroatoms; and for the S and Se capsules, the polarizability of the heteroatoms combines with electric field effects.

Cavitand-Based Pd-Pyridyl Coordination Capsules: Guest-Induced Homo- or Heterocapsule Selection and Applications of Homocapsules to the Protection of a Photosensitive Guest and Chiral Capsule Formation.

A 2 : 4 mixture of tetrakis[4-(4-pyridyl)phenyl]cavitand (1) or tetrakis[4-(4-pyridyl)phenylethynyl]cavitand (2) and Pd(dppp)(OTf)2 self-assembles into a homocapsule {12 ⋅ [Pd(dppp)]4 }8+ ⋅ (TfO- )8 (C1) or {22 ⋅ [Pd(dppp)]4 }8+ ⋅ (TfO- )8 (C2), respectively, through Pd-Npy coordination bonds. A 1 : 1 : 4 mixture of 1, 2, and Pd(dppp)(OTf)2 produced a mixture of homocapsules C1, C2, and a heterocapsule {1 ⋅ 2 ⋅ [Pd(dppp)]4 }8+ ⋅ (TfO- )8 (C3) in a 1 : 1 : 0.98 mole ratio. Selective formation (self-sorting) of homocapsules C1 and C2 or heterocapsule C3 was controlled by guest-induced encapsulation under thermodynamic control. Applications of Pd-Npy coordination capsules with the use of 1 were demonstrated. Capsule C1 serves as a guard nanocontainer for trans-4,4'-diacetoxyazobenzene to protect against the trans-to-cis photoisomerization by encapsulation. A chiral capsule {12 ⋅ [Pd((R)-BINAP)]4 }8+ ⋅ (TfO- )8 (C5) was also constructed. Capsule C5 induces supramolecular chirality with respect to prochiral 2,2'-bis(alkoxycarbonyl)-4,4'-bis(1-propynyl)biphenyls by diastereomeric encapsulation through the asymmetric suppression of rotation around the axis of the prochiral biphenyl moiety.

Mechanically-Driven Vase-Kite Conformational Switch in Cavitand Cross-Linked Polyurethanes.

The eligibility of tetraquinoxaline cavitands (QxCav) as molecular grippers relies on their unique conformational mobility between a closed (vase) and an open (kite) form, triggered in solution by conventional stimuli like pH, temperature and ion concentration. In the present paper, the mechanochemical conformational switching of ad hoc functionalized QxCav covalently embedded in an elastomeric polydimethylsiloxane and in a more rigid polyurethane matrix is investigated. The rigid polymer matrix is more effective in converting mechanical force into a conformational switch at the molecular level, provided that all four quinoxaline wings are covalently connected to the polymer.

Kinetic Stabilities and Exchange Dynamics of Water-Soluble Bis-Formamide Caviplexes Studied Using Diffusion-Ordered NMR Spectroscopy (DOSY).

A deep cavitand binds long-chain trans,trans- and trans,cis-bis-formamide isomers in water solution giving a pair of caviplexes in a ca. 60:40 ratio. Both caviplexes display in/out guest exchange dynamics that are slow on the 1 H NMR chemical shift timescale, but fast on the EXSY timescale. We apply diffusion-ordered NMR spectroscopy (DOSY) to characterize the caviplexes. On the diffusion timescale, the guest in/out exchange processes feature intermediate dynamics allowing the assessment of their kinetic stabilities. We found that the trans,cis-bis-formamide isomers form kinetically more stable caviplexes than the trans,trans-counterparts. We also show that the kinetic stabilities of the bis-formamide caviplexes relate well with their relative thermodynamic stabilities. Fortunately, the tuning of the DOSY parameters allowed the observation of the exchange dynamics as slow processes on the experiment timescale.