Closed Aromatic Tubes-Capsularenes.

In this study, we describe a synthetic method for incorporating arenes into closed tubes that we name capsularenes. First, we prepared vase-shaped molecular baskets 4-7. The baskets comprise a benzene base fused to three bicycle[2.2.1]heptane rings that extend into phthalimide (4), naphthalimide (6), and anthraceneimide sides (7), each carrying a dimethoxyethane acetal group. In the presence of catalytic trifluoroacetic acid (TFA), the acetals at top of 4, 6 and 7 change into aliphatic aldehydes followed by their intramolecular cyclization into 1,3,5-trioxane (1 H NMR spectroscopy). Such ring closure is nearly a quantitative process that furnishes differently sized capsularenes 1 (0.7×0.9 nm), 8 (0.7×1.1 nm;) and 9 (0.7×1.4 nm;) characterized by X-Ray crystallography, microcrystal electron diffraction, UV/Vis, fluorescence, cyclic voltammetry, and thermogravimetry. With exceptional rigidity, unique topology, great thermal stability, and perhaps tuneable optoelectronic characteristics, capsularenes hold promise for the construction of novel organic electronic devices.

Twist-Turn-Twist Motif Chaperoned Inside Molecular Baskets.

Two molecular baskets 16-, each with three (S)-glutamic acids at its rim, were found (NMR, ITC) to complex diammonium alkanes 22+-52+ (+H3N(CH2)nNH3+, n = 7-10) giving ternary [2-5⊂12]10- assemblies (K = 107-109 M-2). From the magnetic perturbation of proton nuclei (1H NMR, NICS), we deduced that each guest assumed a U shape within the binary complex, [2-5⊂1]4-. Two ammonium groups were bound in the "anionic nest" at the top of 16-, while the hydrocarbon chain resided in its nonpolar cavity. From detailed ITC analyses, we showed that the binary complex [2-5⊂1]4- forms first and then another 16- capped [2-5⊂1]4- to give [2-5⊂12]10-, via interactions of the carboxylates at the rims with ammoniums on the guest. Long-range NOEs revealed that U-shaped 22+ and 52+ coiled into highly strained twist-turn-twist formations, for the first time observed within an abiotic host while curiously resembling helix-turn-helix motif found in DNA binding proteins.

On the encapsulation and assembly of anticancer drugs in a cooperative fashion.

In this study, we report the remarkable recognition and assembly characteristics of D 3h symmetric basket 1 6- containing two adjoining and nonpolar cavities with six biocompatible GABA residues at their northern and southern termini. From the results of experimental (1H NMR, fluorescence and UV-Vis spectroscopies) and computational (MM-MC/OPLS3e) investigations, we deduced that hexaanionic 1 6- captured two molecules of anticancer drug doxorubicin 2 + in water and accommodated them in its two deep cavities. The formation of stable 1 6-⊂2 2 2+ (K a = 3 × 1012 M-2) was accompanied by the exceptional homotopic cooperativity (α = 4K 2/K 1 = 112) in which K 1 = 3.2 ± 0.8 × 105 M-1 and K 2 = 9 ± 1 × 106 M-1. Furthermore, bolaamphiphilic 1 6-⊂2 2 2+ assembled into spherical nanoparticles (DLS, cryo-TEM and TEM) possessing 41% drug loading. The preorganization of abiotic receptor 1 6- and its complementarity to 2 + have been proposed to play a part in the positive cooperativity in which ten favorable noncovalent contacts (i.e. hydrogen bonds, salt bridges, C-H···π and π-π contacts) are formed between doxorubicin and the dual-cavity host. In the case of topotecan 3 +, however, the absence of multiple and favorable basket⊂drug interactions resulted in the predominant formation of a binary 1 6- ⊂ 3 + complex (K 1 = 2.12 ± 0.01 × 104 M-1) and the negative homotopic allostery (α ≪ 1). To summarize, our study lays out a roadmap for creating a family of novel, accessible and multivalent hosts capable of complexing anticancer agents in a cooperative manner. As basket⊂drug complexes organize into highly loaded nanoparticles, the reported soft material is amenable to the bottom-up construction of stimuli-responsive nanomedicine capable of effective scavenging and/or delivery of drugs.

Multivalent C-H⋠⋠⋠Cl/Br-C Interactions Directing the Resolution of Dynamic and Twisted Capsules.

In this work, we report a mechanism by which stereoisomeric and twisted capsules P/M-1 direct their dynamic chirality in the presence of haloalkane guests. The capsule comprises a static, but twisted, cage that is linked to a dynamic tris(2-pyridylmethyl)amine (TPA) lid at its top. From the results of experimental (NMR spectroscopy and X-ray crystallography) and computational (DFT) studies, the TPA lid was shown to assume clockwise (+) and counterclockwise (-) folds with diastereomeric (but racemic) capsules M-1(+) and M-1(-) interconverting at a rapid rate (ΔG≠ 189K =9.1 kcal mol-1 ). The relative stability of the capsules was found to be a function of guest(s) residing in their interior (243/262 Å3 ) with small CH2 Cl2 (61 Å3 ) yielding roughly equal population of diastereomeric inclusion complexes. Larger guests, such as CCl4 (89 Å3 ) and CBr4 (108 Å3 ), however, formed M-1(-)⊂CX4 at the expense of M-1(+)⊂CX4 in circa 3:1 ratio. To account for the observation, theory (DFT:M06-2X/6-31+G*) and experiments (1 H NMR spectroscopy) were used to deduce that CX4 guests become localized inside the twisted cage of the capsule by forming a C-X⋅⋅⋅π halogen bond [Nc =d/(rH +rX )=0.91-0.92] with the benzene "floor" while encountering electrostatic repulsions with closer naphthalimide boundaries. At last, the TPA lid used its central methylene hydrogens to establish, within the M-1(-)⊂CX4 , three stabilizing C-H⋅⋅⋅X-C interactions with the guest. The same C-H⋅⋅⋅X-C interactions, however, became weaker (or possibly vanished) after the conformational reorganization of the lid and the formation of less stable M-1(+)⊂CX4 complex. On individual basis, C-H⋅⋅⋅X-C intermolecular contacts are weak and hardly detectable in the solution phase. In the case of capsule P/M-1, however, these contacts were multivalent and altogether strong enough to direct the host's dynamic chirality.

Stackable molecular chairs.

We describe the design, preparation and assembly of chair-shaped molecules, comprising a tris-bicyclo[2.2.1]heptane hub that extends into three phthalimides carrying amino acids or short peptides. In water, molecular chairs stack in an antiparallel manner to give hexavalent dendritic structures, in spite of holding equal charges. The here described strategy for increasing the multivalency of peptides is easy to implement in practice, therefore holding potential for creating novel soft materials and therapeutics.

Stereo- and Regioselective Synthesis of Molecular Baskets.

We describe a stereoselective method for obtaining multigram quantities of molecular basket 1 syn in overall 11% yield, using inexpensive cyclopentadiene and diethyl fumarate as starting materials. First, an asymmetric synthesis of enantioenriched bromo(trimethylstannyl)alkene (-)-8 was accomplished by the stereoselective bromination of dibromonorbornene (+)-4 guided by anchimeric assistance and subsequent syn- exo-elimination of tetrabromonorbornane (-)-5a as the key steps. Subsequent Cu(I)-catalyzed cyclotrimerization of (-)-8 was optimized to give 1 syn/ anti in 85% yield and 1:1 ratio of diastereomers. Importantly, the results of our mechanistic experiments were in line with the cyclotrimerization occurring in a chain-type fashion with racemization of a Cu(I) homochiral dimeric intermediate, reducing the stereoselectivity of the transformation. Enabled by more facile access to molecular baskets of type 1 syn, a range of recognition studies can now be completed for producing novel supramolecular catalysts, organophosphorus scavengers, and nanostructured materials.

Photo-induced formation of organic nanoparticles possessing enhanced affinities for complexing nerve agent mimics.

Molecular baskets 16--36-, functionalized with α-amino acids at their rim, undergo photo-induced α-decarboxylations to give amphiphilic 43--63- assembling into nanoparticles. Nanoparticulate 43--63- possess greater affinities for complexing OPs (akin to sarin and cyclosarin) than monomeric 16--36-. With the ability of nanoparticles to function in urine, our study sets the stage for creating novel nanocarriers capable of spatiotemporal sequestration of nerve agents or pesticides in competitive chemical environments.

Light-Triggered Transformation of Molecular Baskets into Organic Nanoparticles.

Discovering novel and functional photoresponsive materials is of interest for improving controlled release of molecules and scavenging toxic compounds for cleaning our environment or designing chemosensors. In this study, we report on the photoinduced decarboxylation of basket 16- , containing three glutamic acids at its rim. This concave compound is, in an aqueous environment (30 mm phosphate buffer at pH 7.0), monomeric (1 H NMR DOSY, DLS) with glutamic acid residues randomly oriented about its rim (1 H NMR and MM-OPLS3). The irradiation (300 nm) of 16- leads to the exclusive removal of its α-carboxylates to give amphiphilic 23- possessing γ-carboxylates. The photochemical transformation is a consecutive reaction with mono- and bis-decarboxylated products observed with 1 H NMR spectroscopy and ESI mass spectrometry. Amphiphilic 23- is a preorganized molecule (MM-OPLS3) that, in water, aggregates into organic nanoparticles (ca. 50-200 nm in diameter; DLS, TEM and cryo-TEM) having a critical aggregation concentration of 12 µm (UV/Vis). As the transition of monomeric 16- into nanoparticulate 23- is triggered with light, we reasoned that stimuli-responsive formation of the soft material lends itself to nanotechnology applications such as controlled release or scavenging of targeted compounds.

A Hexavalent Basket for Bottom-Up Construction of Functional Soft Materials and Polyvalent Drugs through a "Click" Reaction.

Inspired by polyvalency and its prevalence in nature, we developed an efficient synthetic route for accessing a large variety of multivalent and dual-cavity baskets from inexpensive and abundant starting materials. First, the cycloaddition of vinyl acetate to anthracene was optimized to, upon hydrolysis, give dibenzobarrelene derivative 6, which after five functional group transformations and then cyclotrimerization gave heptiptycene dodecaester 4 in an overall 17 % yield. Following that, compound 4 was converted into D3h symmetric 1, composed of two fused cavitands each holding three terminal alkynes at the rim for conjugation to functional molecules using the highly efficient CuAAC reaction. To survey the reactivity of hexavalent 1, we "clicked" 2-acetamido-2-deoxy-ß-d-glucopyranosyl azide 3,4,6-triacetate (carbohydrate), methoxypolyethylene glycol azide (PEG, Mn =2000; polymer) and benzyl azide (aromatic) to obtain hexavalent conjugates 12-14 in 50-79 % yields. In summary, dual-cavity 1 is an accessible, structurally-unique and hexavalent host that can be "clicked" to a variety of functional molecules for (a) combinatorial lead identification of drugs, (b) preparation of hierarchical soft materials and (c) design of selective chemosensors, scavengers, or supramolecular catalysts.

A Stimuli-Responsive Molecular Capsule with Switchable Dynamics, Chirality, and Encapsulation Characteristics.

In this study, we report the preparation, conformational dynamics, and recognition characteristics of novel molecular capsule 1 comprising a bowl-shaped framework conjugated to a tris(2-pyridylmethyl)amine (TPA) lid. With the assistance of experiment (1H NMR spectroscopy) and theory (MM and DFT) we found that C3 symmetric 1 is poorly preorganized with three pyridines at the rim adopting a propeller-like orientation and undergoing P-to- M (or vice versa) stereoisomerization (Δ G⧧ < 8 kcal/mol, VT 1H NMR). Capsule 1 binds CH4, CH3Cl, CH2Cl2, CHCl3, and CCl4 with Ka < 7 M-1. Protonation of 1 with HCl, however, gives [1·H]-Cl, with the solid-state structure showing the TPA lid being "flattened" and the +N-H---Cl hydrogen-bonded group residing outside. Importantly, the P-to- M stereoisomerization would for [1·H]-Cl occur with Δ G⧧ = 11 kcal/mol (VT 1H NMR). Less dynamic and more preorganized [1·H]-Cl binds CH4, CH3Cl, CH2Cl2, CHCl3, and CCl4 guests with a greater affinity ( Ka = 100-400 M-1) than 1. The results of our studies suggest that the complexation of increasingly larger guests takes place in an induced-fit fashion, with [1·H]-Cl (a) elongating along its vertical axis and concurrently potentially (b) twisting pyridines from P into M (and vice versa) orientation. The addition of Et3N to [1·H]-Cl⊂CH2Cl2 causes deprotonation of the capsule and the release of CH2Cl2 with the process being fully reversed after the addition of HCl. Allosteric capsule 1 with unique structural and dynamic characteristics is expected to, in the future, assist the construction of complex molecular machines and smart functional materials.

Removal of Nerve Agent Simulants from Water Using Light-Responsive Molecular Baskets.

We found that molecular baskets 1-3, with amino acids at their rim, undergo photoinduced decarboxylations to give baskets 4-6 forming a solid precipitate in water. Furthermore, organophosphonates 7-9 (OP), akin in size and shape to G-type nerve agents, form inclusion complexes with baskets 1-3 (K = 6-2243 M-1). Light irradiation (300 nm) of an aqueous solution of 1-3⊂OP led to the formation of precipitate containing an OP compound thereby amounting to a novel strategy for light-induced sequestration of nerve agents or, perhaps, other targeted compounds. Importantly, the stability of basket⊂OP complexes in addition to functional groups at the basket's rim play a role in the efficiency (up to 98%) by which OPs are removed from water.

Examining the Scope and Thermodynamics of Assembly in Nesting Complexes Comprising Molecular Baskets and TPA Ligands.

Molecular baskets capture various tris(2-pyridylmethyl)amine ligands, with and without zinc(II) cation, to form nesting complexes. The results of our computational (MD) and experimental (1H NMR/ITC) studies suggest that the assembly is driven by the hydrophobic effect with the charge of complementary molecular components playing an important role in the formation of nesting complexes. In brief, the complexation only takes place when the basket and the ligand carry either oppositely charged or noncharged groups.

Russian Nesting Doll Complexes of Molecular Baskets and Zinc Containing TPA Ligands.

In this study, we examined the structural and electronic complementarities of convex 1-Zn(II), comprising functionalized tris(2-pyridylmethyl)amine (TPA) ligand, and concave baskets 2 and 3, having glycine and (S)-alanine amino acids at the rim. With the assistance of (1)H NMR spectroscopy and mass spectrometry, we found that basket 2 would entrap 1-Zn(II) in water to give equimolar 1-Zn⊂2in complex (K = (2.0 ± 0.2) × 10(3) M(-1)) resembling Russian nesting dolls. Moreover, C3 symmetric and enantiopure basket 3, containing (S)-alanine groups at the rim, was found to transfer its static chirality to entrapped 1-Zn(II) and, via intermolecular ionic contacts, twist the ligand's pyridine rings into a left-handed (M) propeller (circular dichroism spectroscopy). With molecular baskets embodying the second coordination sphere about metal-containing TPAs, the here described findings should be useful for extending the catalytic function and chiral discrimination capability of TPAs.