Modeling Amine Methylation in Methyl Ester Cavitand.

Methylation of amines inside an introverted resorcinarene-based deep methyl ester cavitand is investigated by means of molecular dynamics simulations and quantum chemical calculations. Experimentally, the cavitand has been shown to bind a number of amines and accelerate the methylation reaction by more than four orders of magnitude for some of them. Eight different amines are considered in the present study, and the geometries and energies of their binding to the cavitand are first characterized and analyzed. Next, the methyl transfer reactions are investigated and the calculated barriers are found to be in generally good agreement with experimental results. In particular, the experimentally-observed rate acceleration in the cavitand as compared to the solution reaction is well reproduced by the calculations. The origins of this rate acceleration are analyzed by computational modifications made to the structure of the cavitand, and the role of the solvent is discussed.

Control of reactivity and selectivity in isomerization and rearrangement reactions inside confined spaces.

In the confined space of supramolecular systems, the substrate can be forced into a reactive conformation and labile intermediates may be stabilized while isolated from the bulk solution. In this highlight, unusual processes mediated by supramolecular hosts are described. These include unfavourable conformational equilibria, unusual product selectivities in bond and ring-chain isomerizations, accelerated rearrangement reactions through labile intermediates, and encapsulated oxidations. In the host, controlled or altered isomerization of the guests can occur via hydrophobic, photochemical and thermal interventions. The inner spaces of the hosts resemble enzyme cavities that stabilize labile intermediates not accessible in the bulk solvent. The effects of confinement and the binding forces involved are discussed and further applications are suggested.

Selective Binding and Isomerization of Oximes in a Self-Assembled Capsule.

A series of straight-chain (C7-C13) alkyl-O-methyl aldoximes (R-C(H)═NOMe) were synthesized with various functional groups at the remote ends (alkenes, halogen, -COOH, and NH2). Their isomers about the C═N bond showed ∼60-40% E-Z-ratio in organic solutions. Surprisingly, their confinement in a water-soluble capsule with benzoselenodiazole walls shows high selectivity for the cis-/Z-isomer. Their relative affinities for the chalcogen-bonded capsule at room temperature depend mainly on the guest chain length and functional groups. A chain length of 14 heavy atoms showed especially high E- to Z-isomer selectivity (>99%) and was used in separation. The E-Z isomerization occurred only in the capsular cavity at room temperature and was accelerated 10-fold by sonication. The Z-isomer selective binding, separation, and E-Z isomerization are supported by NMR, DOSY, and computational studies.

Role of Rim Functions in Recognition and Selectivity of Small-Molecule Guests in Water-Soluble Cavitand Hosts.

Groups on the upper rim of cavitands can play major roles in the recognition of small molecules. Water-soluble deep cavitands 1, 2 or 3 bearing the walls upper rim of imidazole, urea, and methyl urea, respectively, were synthesized and characterized as hosts of small-molecule guests. The vase forms of 1 or 2 are stabilized through H-bonding to solvent water molecules between adjacent walls. Various small alkyl organic molecules - alcohols, halides, cycloalkane derivatives and heterocycles - are efficiently bound in 1. For n-alcohols (C5 to C12), the -OH end is fixed at the upper rim and the alkyl parts are in the hydrophobic cavity. The longer alcohol guests (C7-C12) show coiling. Cycloalkane guests rotate rapidly on all 3 axes within the host cavity, while heterocycles show orientations placing their heteroatoms near the cavitand rim. Competition studies between alkyl chlorides, bromides and iodides showed preference for binding of iodides in 1. Competition between cavitands for hexyl halide guests halide showed the order 2>1>3.

Recent Advances in the Applications of Water-soluble Resorcinarene-based Deep Cavitands.

We review here the use of container molecules known as cavitands for performing organic reactions in water. Central to these endeavors are binding forces found in water, and among the strongest of these is the hydrophobic effect. We describe how the hydrophobic effect can be used to drive organic molecule guests into the confined space of cavitand hosts. Other forces participating in guest binding include cation-π interactions, chalcogen bonding and even hydrogen bonding to water involved in the host structure. The reactions of guests take advantage of their contortions in the limited space of the cavitands which enhance macrocyclic and site-selective processes. The cavitands are applied to the removal of organic pollutants from water and to the separation of isomeric guests. Progress is described on maneuvering the containers from stoichiometric participation to roles as catalysts.

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.

Organic radical reactions confined to containers in supramolecular systems.

Radical chemistry and host-guest chemistry have each developed rapidly over the past decades and their intersection offers an attractive opportunity for modern applications. Radicals can be introduced into the frameworks of supramolecular hosts or radicals can be guests, generated in and confined to host containers. In this highlight we outline research achievements in both approaches, photoinduced and external reagent-initiated radicals in the host. Specific topics include rearrangement and fragmentation reactions, hydrocarbon oxidation and alkyl halide reductions of molecules confined to various supramolecular complexes. Applications to challenging problems in chemical synthesis are suggested.

Rigidified Cavitand Hosts in Water: Bent Guests, Shape Selectivity, and Encapsulation.

We report the synthesis and characterization of two water-soluble container compounds (cavitand hosts) with rigidified open ends. One cavitand uses four (CH2)4's as spacers to bridge the adjacent walls, while another cavitand uses four CH2CH2OCH2CH2's bridges and features a wider open end. The spacers preorganize the deep cavitands into vase-like, receptive shapes and prevent their unfolding to the unreceptive kite-like conformation. Cycloalkane guests (C6-C8) and small n-alkanes (C5-C7) form 1:1 complexes with the cavitands and move freely in the cavitands' spaces. Hydrophilic compounds 1,4-dioxane, tetrahydrofuran, tetrahydropyran, pyridine, and 1-methylimidazole also showed good binding affinity to the new cavitands. Longer alkanes (C11-C14) and n-alcohols (C11-C16) are taken up with a -CH3 group fixed at the bottom of the cavity and the groups near the rim in compressed conformations. The methylene bridges appear to divide the cavitand into a narrow hydrophobic compartment and a broader space with exposure to the aqueous medium. Longer alkane guests (C15-C18), N,N-dimethyldioctylammonium, and dioctylamine induce the formation of capsules (2:1 host:guest complexes). The new cavitands showed selectivity for p/m-cresol isomers and xylene isomers. The cavitand with CH2CH2OCH2CH2 bridges bound long-chain α,ω-diols (C13-C15) and diamines in folded, U-shaped conformations with polar functions exposed to the aqueous medium. It was used to separate o-xylene from its isomers by using simple extraction procedures.

The role of electric field, peripheral chains, and magnetic effects on significant 1H upfield shifts of the encapsulated molecules in chalcogen-bonded capsules.

The chalcogen-bonded homo-cavitand and hetero-cavitand AY+AY' capsules (Y, Y' = Se, Te), as well as their encapsulated complexes with one or two guest molecules have been studied theoretically via density functional theory (DFT), while the 1H NMR spectra of the homo-cavitand encapsulated complexes (in ASe+ASe) have been measured experimentally. There is excellent agreement between theoretical and experimental spectra. In all cases, we found significant 1H upfield shifts which are more intense in the ASe+ASe cage compared to the ATe+ATe and ASe+ATe cages. The non-uniform electron distribution which gives rise to an inherent electric field and a non-zero electric dipole moment of the encapsulated complexes, the induced electric field effects, the magnetic anisotropy which is enhanced due to the polarizability of chalcogen atoms, and the peripheral chains, which are responsible for the solubility of the cages, increase the upfield shifts of 1H of the encapsulated molecules; the peripheral chains lead to an increase of the upfield shifts by up to 1.8 ppm for H of the rim and up to 1.2 ppm for the terminal H in the interior of the cage. Hence, substantial 1H upfield chemical shifts of the guests in these capsules are consequences of (i) the enhanced aromaticity of the walls of the capsules due to the polarizability of chalcogen atoms, (ii) the induced and inherent electric field effects, and (iii) the peripheral chains.

Water and the Cation-π Interaction.

The cation-π interaction and the hydrophobic effect are important intermolecular forces in chemistry and play major roles in controlling recognition in biological systems. We compared their relative contributions to the binding of molecular "dumbbell" guests in synthetic container hosts in water. The guests offered direct, intramolecular competition between trimethylammonium groups, -N+(CH3)3, and tert-butyl groups, -C(CH3)3, for the internal surfaces (aromatic panels) of the containers. In contrast with previous studies, the container molecules consistently preferred binding to the uncharged tert-butyl groups, regardless of the presence of anionic, cationic, or zwitterionic groups on the container peripheries. This preference is determined by solvation of the polar trimethylammonium group in water, which outcompetes the attraction between the positive charge and the π-surfaces in the container. The synthetic container complexes provide a direct measure of the relative strengths of cation-π interactions and desolvation in water. Interactions with the uncharged tert-butyl group are more than 12 kJ mol-1 more favorable than the cation-π interactions with the trimethylammonium group in these cavitand complexes.

Recognition of hydrophilic molecules in deep cavitand hosts with water-mediated hydrogen bonds.

We describe new container host molecules - deep cavitands with benzimidazole walls and ionic feet - to recognize highly hydrophilic guest molecules in water. The aromatic surfaces of the cavity recognize hydrophobic portions of the guest while bound water molecules mediate hydrogen bonding in the complex. Spectroscopic (NMR) evidence indicates slow in/out exchange on the chemical shift timescale and thermodynamic (ITC) methods show large association constants (Ka up to 6 × 104 M-1) for complexation of small, water-soluble molecules such as THF and dioxane. Quantum chemical calculations are employed to optimize the host-guest geometries and elucidate the hydrogen bonding patterns responsible for the binding.

Hydrophobic and Metal-Coordinated Confinement Effects Trigger Recognition and Selectivity.

We report the synthesis and characterization of a new water-soluble cavitand 1. The container features 2-aminobenzimidazole panels at the "rim" and pyridiniums at the "feet". In the solid state, a single-crystal X-ray structure of the organic-soluble precursor 2 showed a stable vase form. The structure is stabilized by hydrogen-bonded bridges between adjacent panels through solvents and ions. In aqueous solution, binding of hydrophobic and amphiphilic guest molecules to 1 was investigated using 1H NMR. Alkanes, alcohols, acids, diols, and diacids formed 1:1 host-guest complexes, and the guest conformations were deduced from characteristic chemical shift changes. In the presence of [Pd(ethylenediamine)(H2O)2·2NO3], cavitand 1 formed a complex incorporating two metals. The metal-coordinated cavitand also bound hydrophobic linear alkanes and difluorobenzene isomers in aqueous medium. The metallo-cavitand showed shape and size selectivity and was used to separate o-difluorobenzene from its isomers as observed by 19F NMR spectroscopy. The primary amino function of the cavitands offers possibilities for further elaboration to covalent clusters of these container compounds.

Recognition of Hydrophilic Cyclic Compounds by a Water-Soluble Cavitand.

A water-soluble deep cavitand bearing amides on the upper rim and trimethyl ammonium groups on the feet was synthesized. The open-ended cavity is stabilized by the intramolecular hydrogen bonds formed between the adjacent amides, and the introduction of trimethylammonium imparts to the cavitand good solubility in water. The cavitand exhibits high binding affinity and selectivity to hydrophilic molecules in water. With certain guests, such as cyclohexyl alcohols, amines and acids, the recognition involves the synergistic action of hydrogen bonding with hydrophobic effects. The binding phenomena are interpreted in terms of a fixed solvent cage presented by the host to the guest.

Dimeric capsules self-assembled through halogen and chalcogen bonding.

Supramolecular capsules are nanoscale containers useful for the study of molecular behavior in confined spaces. They offer practical applications in catalysis, molecular transport, drug delivery, and materials science. Self-assembly has proven to be an effective approach in constructing supramolecular capsules and a variety of well-known noncovalent interactions including hydrogen bonding, metal coordination and ionic interactions have been deployed. Bowl-shaped cavitand structures built up from resorcinarenes have particular advantages for the construction of supramolecular capsules, and this highlight discusses the unconventional self-assembly of molecular capsules held together by halogen and chalcogen bonds.

Selective Macrocycle Formation in Cavitands.

The traditional end-to-end cyclization of long-chain linear precursors is difficult and often unpredictable because the unfavorable entropy of macrocyclic closure allows undesired intermolecular reactions to compete. Here, we apply cavitands to the selective intramolecular aldol/dehydration reaction of long-chain α,ω-dialdehydes in aqueous solution. Hydrophobic forces drive the dialdehydes into the cavitands in folded conformations and favor macrocyclization reactions over intermolecular reactions observed in bulk solution. The macrocyclic aldol reaction products are isolated in good yields (30-85%) over a wide range (11 to 17-membered rings). Unlike conventional templates that become guests inside their assembled hosts, cavitands reverse the roles and resemble the situation in biological catalysis-the templates are hosts for guests undergoing the assisted reaction processes.

Highly Selective Radical Monoreduction of Dihalides Confined to a Dynamic Supramolecular Host.

Reduction of alkyl dihalide guests (2-5 and 7) with trialkylsilanes (R3 SiH) was performed in water-soluble host 1 to investigate the effects of confinement on fast radical reactions (k≥103 m-1 s-1 ). High selectivity (>95 %) for mono-reduced products was observed for primary and secondary dihalide guests under mild conditions. The results highlight the importance of host-guest complexation rates to modulate the product selectivity in radical reactions.

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.

Confined molecules: experiment meets theory in small spaces.

The behavior of molecules confined to small spaces is fascinating chemistry and lies at the heart of signaling processes in biology. Our approach to confinement is through reversible encapsulation of small molecules in synthetic containers. We show that confinement leads to amplified reactivities in bimolecular reactions, stabilization of otherwise reactive species, and limitation in motions that create new stereochemical arrangements. The isolation of molecules from solvent makes for manageable computations and has stimulated theorist to examine reaction details in the limited space. Transition states for reactions and rearrangements can be calculated, the effects of (de)solvation can be evaluated and the magnetic properties of the containers can be compared with experimental observations. Finally, we outline several potential applications, including entanglement chemistry and the use of isomers in data storage.

Binding selectivity and separation of p-functionalized toluenes with a metallo-cavitand in water.

A metallo-cavitand (1-2Pd) showed unprecedented binding selectivity and sequestration of p-functionalized toluene isomers in water. The host-guest complexation was studied using 1H and COSY NMR methods and xylene-isomer complexes were examined by using DFT calculations. A liquid-liquid extraction scheme was developed for the separation of p-functionalized toluenes.

Modeling the Reaction of Carboxylic Acids and Isonitriles in a Self-Assembled Capsule.

Quantum chemical calculations were used to study the reaction of carboxylic acids with isonitriles inside a resorcinarene-based self-assembled capsule. Experimentally, it has been shown that the reactions between p-tolylacetic acid and n-butyl isonitrile or isopropyl isonitrile behave differently in the presence of the capsule compared both with each other and also with their solution counterparts. Herein, the reasons for these divergent behaviors are addressed by comparing the detailed energy profiles for the reactions of the two isonitriles inside and outside the capsule. An energy decomposition analysis was conducted to quantify the different factors affecting the reactivity. The calculations reproduce the experimental findings very well. Thus, encapsulation leads to lowering of the energy barrier for the first step of the reaction, the concerted α-addition and proton transfer, which in solution is rate-determining, and this explains the rate acceleration observed in the presence of the capsule. The barrier for the final step of the reaction, the 1,3 O→N acyl transfer, is calculated to be higher with the isopropyl substituent inside the capsule compared with n-butyl. With the isopropyl substituent, the transition state and the product of this step are significantly shorter than the preceding intermediate, and this results in energetically unfavorable empty spaces inside the capsule, which cause a higher barrier. With the n-butyl substituent, on the other hand, the carbon chain can untwine and hence uphold an appropriate guest length.