Molecular Capsules Research Articles

Self-Assembly of Nanocubic Molecular Capsules via Solvent-Guided Formation of Rectangular Blocks.

We investigate the mechanism underlying the self-assembly of gear-shaped amphiphilic molecules into a highly ordered nanocubic capsule ("nanocube") in aqueous methanol. Simulation results show that the solvent molecules play a significant role in the assembly process by directing the primitive intermediates to orthogonal/rectangular shapes, thus creating appropriate building blocks for cubic assembly while avoiding off-pathway stacked aggregates. Free-energy analyses reveal that the interplay of the direct intermonomer interaction and the solvent-mediated repulsion between large aromatic cores (via preferential solvation of methanol on hydrophobic surfaces) leads to the strong trend for perpendicular binding of monomers and hence the solvent-guided formation of rectangular blocks. Furthermore, we report the self-assembly simulation of the nanocube using replica exchange with solute tempering and demonstrate that the simulation can predict a highly ordered nanocapsule structure, assembly intermediates, and encapsulated molecules, which helps promote computer-aided design of functional molecular self-assemblies in explicit solvent.

Catalysis inside the Hexameric Resorcinarene Capsule

In this Account, we outline our investigation into the supramolecular resorcinarene capsule as a catalyst. Molecular capsules not only are of interest due to the similarities of their binding pockets with those of natural enzymes but also feature potential advantages for catalysis. Due to the restricted internal volume of the binding pockets, substrate selectivities are commonly observed. Substrates that are encapsulated more efficiently will be converted selectively in the presence of less suitable substrates. This size selectivity cannot be obtained in a regular solution experiment. In addition, because of the distinct chemical environment inside the capsule, different product selectivities may be observed. Furthermore, the encapsulation of reactive catalysts inside confined environments may improve catalyst compatibility for multicatalyst tandem reactions. Although the potential advantages of performing catalysis inside closed microenvironments are generally recognized, the number of known catalytically active supramolecular host systems is still very limited. There are several reasons, the most important of which is that it is very difficult to predict the catalytic potential of known supramolecular host systems. In several cases, even the encapsulation behavior of host systems is not completely understood or explored. Therefore, it is evident that further research is required to explore the potential of catalysis inside supramolecular capsules. Our initial research mainly focused on understanding the puzzling encapsulation behavior of the self-assembled resorcinarene capsule I and the closely related pyrogallolarene capsule II. After the elucidation of the decisive differences between these two systems, we explored the catalytic potential of capsule I. A variety of different reactions were successfully performed inside its cavity. The most important examples highlighted in this Account are iminium catalysis, the tail-to-head terpene cyclization, and the carbonyl-olefin metathesis. In the case of proline-mediated iminium catalysis, we were able to demonstrate that the enantioselectivity for the product formation was increased when the reaction was performed inside the cavity of capsule I. This is remarkable since the capsule is formed from achiral building blocks and, therefore, does not add chiral information to the reaction mixture. The tail-to-head terpene cyclization is the most complex reaction performed so far inside capsule I. The cyclic monoterpenes eucalyptol and α-terpinene were formed in useful yields. Interestingly, these products have not yet been synthetically accessible in solution directly from acyclic terpene precursors. Furthermore, we demonstrated that the cocatalytic system of capsule I and HCl is suitable for carbonyl-olefin metathesis. HCl was shown to be an inefficient catalyst for this reaction in solution experiments. This demonstrates that the different chemical environment inside the supramolecular container can lead to altered product selectivity. In general, we hope to demonstrate in this Account that research on catalysis inside supramolecular capsules, although still in its infancy, is starting to produce the first synthetically relevant results.

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.

Control of Heterometallic Three‐Dimensional Macrocycles with Aromatic Stacks in Tunable Host Cavities

Using coinage metal (Cu(II), Ag(I)) hinges, two sets of heterometallic molecular capsules with analogous open‐ended cavities were prepared based on the half‐sandwich rhodium fragments. In the case of [Rh4Cu4] cages, up to six‐fold‐stacked host‐guest structures were formed by varying the cavity's dimensions. Moreover, the series of capsules were demonstrated to self‐fine‐tune to form multi‐heteroguest arrays via favourable donor‐acceptor π interactions and Ag‐π interactions, as evidenced from single‐crystal X‐ray analysis.

Designing Helical Molecular Capsules Based on Folded Aromatic Amide Oligomers.

The ab initio rational structure-based design of a synthetic molecular receptor for a given complex biomolecular guest remains an elusive objective, yet remarkable progress has been achieved in recent years. This Account deals with the use of folded artificial aromatic amide oligomers, also termed aromatic foldamers, inspired from biopolymer structures, for the design of helical molecular capsules that can recognize guest molecules, completely surround them, and isolate them from the solvent, thus giving rise to a sort of guest encapsulation associated with slow binding and release kinetics. The development of new amino acid, diacid, and diamine monomers, a main source of creativity in this field, progress in their assembly into ever longer oligoamide sequences, and the predictability of the folded structures due to their inherent rigidity and simple folding principles, allowed for the design and preparation of unimolecular and bimolecular capsule shapes. These capsules consist of molecular helices having a large diameter in the middle and a narrow diameter at both ends thus creating a cavity suitable for binding a guest molecule. The understanding of molecular recognition properties within these bioinspired containers has greatly progressed. Recognition of simple guests such as diols or amino-alcohols may thus be predicted, and hosts can be proposed for guests as complex as saccharides using first principle design. Taking advantage of the modular nature of oligomeric sequences, of their synthetic accessibility and of their propensity to grow into crystals suitable for X-ray crystallographic analysis, a structure-based iterative design methodology has been developed that eventually yielded exquisite guest selectivity, affinity, and diastereoselectivity. This methodology involves rational negative design steps during which changes in the foldamer capsule sequence are not intended to improve binding to the targeted guest but instead to exclude the binding of other guests while preserving key interactions with the target. Metal ions can also be introduced at the inner rim of foldamer capsules and eventually assist the binding of an organic guest. These results demonstrate the viability of an ab initio approach to abiotic receptor design based on aromatic foldamers. The dynamic of the capsules associated with their self-organized nature provides opportunities to not only tune guest binding and selectivity, but also guest capture and release kinetics as well as cavity size and shape. Controlled release thus emerges as a realistic objective. Recent progress thus opens up multiple perspectives for the development of tailored hosts, sensors, and carriers structurally and conceptually different from earlier generations of macrocyclic-based receptors or from supramolecular containers produced by self-assembly.

Aerobic Electrochemical Oxygenation of Light Hydrocarbons Catalyzed by an Iron–Tungsten Oxide Molecular Capsule

The selective oxidation of light hydrocarbons and their valorization with only dioxygen (O2) are important transformations toward development of efficient chemical processes. Monooxygenase enzymes can catalyze selective aerobic reactions under reducing and protic conditions. The translation of such enzymatic pathways to the practical electrocatalytic oxidation of light, gaseous hydrocarbons, using O2 as sole oxidant is now reported. An iron–tungsten oxide inorganic molecular catalyst with a capsular structure {Fe30W72} stabilized inside by sulfate/bisulfate anions provides a protic environment where three iron atoms are located at each of the pores of the capsule leading to a unique and potent active site for the oxidation reactions. Under mild electrochemical conditions, 1.8 V, in water at room temperature, using O2 from air, we demonstrate the low-pressure (1–2 bar) hydroxylation of alkanes, notably ethane to acetic acid, and the ozone like cleavage of the carbon–carbon double bonds of alkenes. Typical ...

Stacking-interaction-induced host-guest chemistry and Borromean rings based on a polypyridyl ligand.

Template-free molecular Borromean rings (BRs) and open-ended molecular capsules were realized by strategic selection of the polypyridyl ligand tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j] phenazine (TPPHZ) with a large surface area and specific geometry. The topology of these intricate architectures was constructed via precisely controlled stacking interactions, as evidenced from single-crystal X-ray analysis.

Self-Assembly of a Tetraphenylethylene-Based Capsule Showing Both Aggregation- and Encapsulation-Induced Emission Properties.

Functional molecular capsules have attracted a lot of attention in recent years because of their potential applications as chemosensors, catalysis, drug carriers, and so on. We report here the coordination-directed self-assembly of a fluorescent-lantern-type molecular capsule from four tetraphenylethylene-based ditopic ligands and two square-planar palladium(II) ions. The capsule has been thoroughly characterized by UV-vis, 1D/2D NMR, electrospray ionization time-of-flight mass spectrometry, and single-crystal X-ray diffraction studies. The aggregation-induced emission performance of the capsule has been studied by tuning the ratio of mixed solvents. Moreover, with an open cavity, the fluorescence of the capsule also displays anion sensitivity, with the best turn-on responsiveness observed for HCO3-, demonstrating for the first time an encapsulation-induced emission property.

Interlaced capsules by self-assembly of cavitands substituted with tripeptides and tetrapeptides

A strategy that utilizes macrocyclic resorcin[4]arenes for the pre-positioning of peptides to form cavitands that subsequently self-assemble through hydrogen bonds was used for the formation of molecular capsules. Hydrophobic tri- and tetrapeptides were attached via their C-termini to tetraformylresorcin[4]arene using acylhydrazone linkers. The resulting cavitands self-assemble in relatively non-polar environments (chloroform or chloroform-methanol) forming non-covalent dimers through hydrogen bonding motifs resembling beta-sheets. NMR studies (ROESY and DOSY) indicate that the binding motif involves C-terminal amino acids from the peptide strands, while the N-terminal parts are positioned outside of the cavity. The capsules possess stable porous structures and they are able to quantitatively complex fullerenes C60 and C70.

Quantifying Guest Exchange in Supramolecular Systems

AbstractThe ability to accurately determine and quantitatively evaluate kinetic phenomena associated with supramolecular assemblies, in real time, is key to a better understanding of their defined architectures and diverse functionalities. Therefore, analytical tools that can precisely assess a wide range of exchange rates within such systems are of considerable importance. This study demonstrates the ability to use an NMR approach based on saturation transfer for the determination of rates of guest exchange from molecular capsules. By using cavitands that assemble into distinct dimeric assemblies, we show that this approach, which we term guest exchange saturation transfer (GEST), allows the use of a conventional NMR setup to study and quantitatively assess a wide range of exchange rates, from 35 to more than 5000 s−1.

Molecular capsules of tetrakis(N-hydantoinylimino)cavitand: Selective encapsulation of 1,4-diiodobenzene

Resorcin[4]arene-based iminocavitand 2 with four hydantoinyl moieties was designed and synthesized. This cavitand 2 self-assembled into thermally stable molecular capsules G@22 in the presence of suitable guests through 8 intermolecular hydrogen bonds of imide NH⋯OC, two for each four paired hydantoinyl units. Molecular capsule 22 showed selective complexation for p-disubstituted benzenes, especially for 1,4-diiodobenzene.

What Is the Optoelectronic Effect of the Capsule on the Guest Molecule in Aqueous Host/Guest Complexes? A Combined Computational and Spectroscopic Perspective

Encapsulation of dye molecules is used as a means to achieve charge separation across different dielectric environments. We analyze the absorption and emission spectra of several coumarin molecules that are encapsulated within an octa-acid dimer forming a molecular capsule. The water-solvated capsule effect on the coumarin’s electronic structure and absorption spectra can be understood as due to an effective dielectric constant where the capsule partially shields electrostatically the dielectric solvent environment. Blue-shifted emission spectra are explained as resulting from a partial intermolecular charge transfer where the capsule is the acceptor, and which reduces the coumarin relaxation in the excited state.

Polyaromatic molecular peanuts

Mimicking biological structures such as fruits and seeds using molecules and molecular assemblies is a great synthetic challenge. Here we report peanut-shaped nanostructures comprising two fullerene molecules fully surrounded by a dumbbell-like polyaromatic shell. The shell derives from a molecular double capsule composed of four W-shaped polyaromatic ligands and three metal ions. Mixing the double capsule with various fullerenes (that is, C60, C70 and Sc3N@C80) gives rise to the artificial peanuts with lengths of ∼3 nm in quantitative yields through the release of the single metal ion. The rational use of both metal–ligand coordination bonds and aromatic–aromatic π-stacking interactions as orthogonal chemical glue is essential for the facile preparation of the multicomponent, biomimetic nanoarchitectures.

From Mixed-Valent Phenyltellurenyl Bromide Ph(Br2)TeTePh to the Isolation of [{(C6H5)Te}19O24Br5]Br4

The σ-donor ligand selone L (L = 1,3-dibutylbenzimidazolin-2-selone, C15H22N2Se) caused cleavage of the Te–Te bond of the mixed-valent phenyltellurenyl bromide {Ph(Br2)TeTePh} in THF to produce the selone adduct of a phenyltellurenyl cation with phenyltellurium dibromide anion, [PhTe(L)][PhTeBr2] (1). The adduct disproportionated in polar solvent (CH3CN), followed by hydrolysis with traces of water to give the largest telluroxane cluster, [{(C6H5)Te}19O24Br5]Br4, with a Te19O24 skeleton. The bowl-shaped telluroxane cluster dimerizes in the solid state, forming the molecular capsule {[{(C6H5)Te}19O24Br5]Br4}2. The cluster is amphipathic and has a hydrophilic cavity consisting of tellurium, oxygen, and bromide atoms, which contains 24H2O molecules.

Metal‐Coordination‐Assisted Folding and Guest Binding in Helical Aromatic Oligoamide Molecular Capsules

AbstractThe development of foldamer‐based receptors is driven by the design of monomers with specific properties. Herein, we introduce a pyridazine‐pyridine‐pyridazine diacid monomer and its incorporation into helical aromatic oligoamide foldamer containers. This monomer codes for a wide helix diameter and can sequester metal ions on the inner wall of the helix cavity. Crystallographic studies and NMR titrations show that part of the metal coordination sphere remains available and may then promote the binding of a guest within the cavity. In addition to metal coordination, binding of the guest is assisted by cooperative interactions with the helix host, thereby resulting in significant enhancements depending on the foldamer sequence, and in slow guest capture and release on the NMR time scale. In the absence of metal ions, the pyridazine‐pyridine‐pyridazine monomer promotes an extended conformation of the foldamer that results in aggregation, including the formation of an intertwined duplex.

Metal‐Coordination‐Assisted Folding and Guest Binding in Helical Aromatic Oligoamide Molecular Capsules

The development of foldamer-based receptors is driven by the design of monomers with specific properties. Herein, we introduce a pyridazine-pyridine-pyridazine diacid monomer and its incorporation into helical aromatic oligoamide foldamer containers. This monomer codes for a wide helix diameter and can sequester metal ions on the inner wall of the helix cavity. Crystallographic studies and NMR titrations show that part of the metal coordination sphere remains available and may then promote the binding of a guest within the cavity. In addition to metal coordination, binding of the guest is assisted by cooperative interactions with the helix host, thereby resulting in significant enhancements depending on the foldamer sequence, and in slow guest capture and release on the NMR time scale. In the absence of metal ions, the pyridazine-pyridine-pyridazine monomer promotes an extended conformation of the foldamer that results in aggregation, including the formation of an intertwined duplex.

Electronic Structure Studies on the Whole Keplerate Family: Predicting New Members.

A comprehensive study of the electronic structure of nanoscale molecular oxide capsules of the type [{MVI (MVI )5 O21 }12 {M'V2 O2 (μ-X)(μ-Y)(Ln- )}30 ](12+n)- is presented, where M,M'=Mo,W, and the bridging ligands X,Y=O,S, carried out by means of density functional theory. Discussion of the electronic structure of these derivatives is focused on the thermodynamic stability of each of the structures, the one having the highest HOMO-LUMO gap being M=W, M'=Mo, X=Y=S. For the most well-known structure M=M'=Mo, X=Y=O, [Mo132 O372 ]12- , the chemical bonding of several ligands to the {MoV2 O2 (μ-O)2 } linker moiety produces negligible effects on its stability, which is evidence of a strong ionic component in these bonds. The existence of a hitherto unknown species, namely W132 with both bridging alternatives, is discussed and put into context.

Self-Assembling Molecular Capsules Based on α,γ-Cyclic Peptides.

A new capsule based on a β-sheet self-assembling cyclic peptide with the ability to recognize and release several guests is described. The host structure is composed of two self-complementary α,γ-cyclic peptides bearing a Zn porphyrin cap that is used for the selective recognition of the guest. The two components are linked through two dynamic covalent bonds. The combination of binding forces, including hydrogen bonding, metal coordination, and dynamic hydrazone bonds, allows the reversible recognition of long bipyridine guests. The affinity for these ligands showed a strong dependence on the guest length. Delivery of the encapsulated ligand can be achieved by hydrolysis of hydrazones to disrupt the sandwich complex structure.

A pH-responsive molecular capsule with an acridine shell: catch and release of large hydrophobic compounds.

Unlike common polyaromatic hydrocarbons, acridine is a characteristic compound bearing both π-stackable large surfaces and a protonable nitrogen atom. Here we report the first synthesis of a supramolecular capsule with multiple acridine panels. In water, the assembly and disassembly of the capsule reversibly occur under neutral and acidic conditions, respectively (≥10 cycles). Notably, the pH-responsive capsule encapsulates a variety of large hydrophobic compounds (up to 1.6 nm in diameter) such as coumarins, metallophthalocyanines and subphthalocyanine in neutral water and subsequently releases them by simple addition of acid.

Hydrogen-bonded molecular capsules: probing the role of water molecules in capsule formation in modified cyclotricatechylene

Pyridine moiety-appended doubly bridged cyclotricatechylene (CTC(Py)2(OH)2) was synthesized and characterized. Solid state studies show that CTC(Py)2(OH)2 forms a capsular assembly in the presence of water but a polymeric assembly in its absence.