Enthalpy-entropy compensation reveals solvent reorganization as a driving force for supramolecular encapsulation in water

A chiral self-assembled M4L6 host assembly has been shown to be a suitable host for the supramolecular encapsulation of a series of guests in polar solvents, ranging from simple organic ammonium cations to more complex organometallic species. This molecular recognition process creates highly selective reactivity within the host cavity. In order to understand the factors driving the molecular recognition process, the standard thermodynamic parameters for encapsulation were determined for a series of protiated and fluorinated iridium guests in a variety of polar solvents using van't Hoff analysis. The encapsulation process for these guests exhibited enthalpy-entropy compensation effects. In solvents such as water and methanol, error analysis suggests a chemical origin for this behavior. In contrast, error analysis of this compensation behavior in polar aprotic solvents such as dimethyl sulfoxide reveals that this correlation is due to an artifact inherent in the intrinsic correlation between the enthalpy and entropy terms in the van't Hoff analysis. Guest encapsulation in polar protic solvents such as water appears to be driven by initial desolvation of the guest with concomitant rearrangement of the hydrogen bond networks in solution. This behavior shares common characteristics with other synthetic and natural host-guest and molecular recognition processes in aqueous solution, ranging from simple crown ether to complex enzyme-ligand interactions.     

An NMR study of the rates of single-molecule exchange in a cylindrical host capsule

Self-assembled cylindrical capsule 1 is reversibly formed from dimerization of two tetraimide resorcinarenes. Studies of guest exchange involving host capsule 1 reveal a mechanistic continuum for exchange that depends on the structure of the guest. Kinetic and dynamic NMR measurements demonstrate the direct displacement of one guest by another. Surprisingly, in the case of benzene exchange in the pairwise encapsulation of benzene and p-xylene, the incoming benzene occupies the same half of the capsule as the outgoing benzene. As the size of the guests increases, solvent-bridged intermediates determine the rates; empty volumes on the molecular scale need not be invoked.     

Guest encapsulation and self-assembly of a cavitand-based coordination capsule

The synthesis and spectroscopic characterization of a cavitand-based coordination capsule 14 BF4 of nanometer dimensions is described. Encapsulation studies of large aromatic guests as well as aliphatic guests were performed by using 1H NMR spectroscopy in [D1]chloroform. In addition to the computational analysis of the shape and geometry of the capsule, an experimental approach to estimate the interior size of the cavity is discussed. The cavity provides a highly rigid binding space in which molecules with lengths of approximately 14 A can be selectively accommodated. The rigid cavity distinguished slight structural differences in the flexible alkyl-chain guests as well as the rigid aromatic guests. The detailed thermodynamic studies revealed that not only CH-pi interactions between the methyl groups on the guest termini and the aromatic cavity walls, but also desolvation of the inner cavity play a key role in the guest encapsulation. The cavity preferentially selected the hydrogen-bonded heterodimers of a mixture of two or three carboxylic acids 18-20. The chiral capsule encapsulated a chiral guest to show diastereoselection.     

Reversible guest exchange mechanisms in supramolecular host-guest assemblies

Synthetic chemists have provided a wide array of supramolecular assemblies able to encapsulate guest molecules. The scope of this tutorial review focuses on supramolecular host molecules capable of reversibly encapsulating polyatomic guests. Much work has been done to determine the mechanism of guest encapsulation and guest release. This review covers common methods of monitoring and characterizing guest exchange such as NMR, UV-VIS, mass spectrometry, electrochemistry, and calorimetry and also presents representative examples of guest exchange mechanisms. The guest exchange mechanisms of hemicarcerands, cucurbiturils, hydrogen-bonded assemblies, and metal-ligand assemblies are discussed. Special attention is given to systems which exhibit constrictive binding, a motif common in supramolecular guest exchange systems.     

Molecular encapsulation in pyrogallolarene hexamers under nonequilibrium conditions

Pyrogallol[4]arene is a macrocycle with a concave surface and 12 peripheral hydroxyl groups that mediate its self-assembly to form hexamers of octahedral symmetry in the solid state, in solution, and in the gas phase. These hexamers enclose approximately 1300 ?(3) of space, which is filled with small molecules. In this study, we show that solvent-free conditions for guest entrapment in these hexamers, using molten guest molecules as solvent and allowing the capsules to assemble during cooling, results in exceptionally kinetically stable encapsulation complexes that are not formed in the presence of solvent and are not thermodynamically stable. The capsules' kinetic stabilities are strongly dependent on the size and shape of both guest and solvent molecules, with larger or nonplanar molecules with rigid geometries providing enhanced stability. The greatest observed barrier to guest exchange, ΔG(?) = 32 ± 0.7 kcal mol(-1) for encapsulated CCl(4) → encapsulated pyrene, is, to the best of our knowledge, indicative of the most powerful kinetic trap ever observed for a synthetic, hydrogen-bonded encapsulation complex. Detailed NMR studies of the structures of the assemblies and the kinetics and mechanisms for guest exchange reveal that subtle differences in guest and solvent structure can impart profound effects on the behavior of the systems. Kinetic and thermodynamic stability, capsule symmetry and structure, guest tumbling rates, susceptibility to disruption by polar solvents, and even the mechanism for equilibration-the presence or absence of supramolecular intermediates-are all greatly influenced. The strongest observed kinetic traps provide encapsulation complexes that are not at equilibrium but are nonetheless indefinitely persistent at ambient temperatures, a property that invites future applications of supramolecular chemistry in open systems where equilibrium is not possible.     

Capsule-like assemblies in polar solvents

Calix[4]arene derivatives with four anionic groups at their upper rim form discrete 1:1 complexes with complementary calix[4]arene derivatives bearing four cationic groups at their upper rim. Each cation is bound by two anions, and vice versa, in a mutual chelate arrangement, reinforced by a network of ionic hydrogen bonds. These multiple electrostatic interactions lead to the formation of highly stable capsule-like assemblies even in polar protic solvents such as methanol and water. In the capsule interior a cavity is formed that is in principle large enough for the encapsulation of small aliphatic and aromatic guests (170-230 A(3)). Monte Carlo simulations in water reproducibly lead to the same regular opimized structures. These differ mainly by their inner volume and flexibility, as demonstrated by molecular dynamics calculations. Most half-spheres can be synthesized by way of the tetrakis(chloromethyl) or the tetrabromocalix[4]arene intermediate. Oppositely charged calix[6]arenes also form strong complexes, but no indication was found for a lock in the cone conformation. The formation of the ball-shaped complexes from calix[4]arene building blocks was studied with Job plots, NMR titrations, NOESY, and variable-temperature experiments, as well as ESI-MS measurements. Investigations aimed at the inclusion of various guest molecules were carried out with alcohols, sulfoxides, benzene derivatives, and ammonium, as well as pyrazinium guests. Although binding isotherms were generated with cationic guests, these must be considered to be loosely associated around the seam rather than included inside the capsule.     

Structure, stability and guest affinity of tris(3-ureidobenzyl)amine capsules in solution

In non-competitive solvents, the tris(3-ureidobenzyl)amines 1 a-c form dimeric assemblies in which guests such as CH(3)CN, CH(3)NO(2), CH(2)Cl(2), CH(3)I, CH(2)BrCl, CH(2)Br(2), CHCl(3) and C(6)H(6) can be encapsulated. Variable temperature (1)H and (1)H,(1)H-ROESY NMR spectroscopy, as well as pulsed-gradient spin-echo (PGSE) diffusion measurements were used to investigate the encapsulation within 1 a1 a (1 a: tris{3-[N'-(4-butylphenyl)ureido]benzyl}amine). Kinetic parameters for the encapsulation of CH(3)NO(2), CH(2)Cl(2) and CH(3)I, both in CDCl(3) and in [D(8)]toluene have been obtained by using magnetisation transfer methods. These data are discussed together with the thermodynamic parameters. The affinity between guest and capsule seems to be dictated mainly by the electronic, size and shape complementarity between cavity and guest. A gating mechanism for guest exchange is proposed.     

Kinetics and thermodynamics of hexameric capsule formation

Resorcinarene 1b forms a hexameric assembly in water-saturated CDCl(3) that encapsulates one tetraalkylammonium salt (2(+)Br(-)). The remaining space is occupied by coencapsulated solvent molecules. A maximum of three and minimum of one CHCl(3) molecule were found inside of capsules with tetrapropyl- and tetraheptylammonium bromide, respectively. The encapsulation of the salt is endothermic and entropically favored by the liberation of the solvent molecules. The stabilities of the encapsulation complexes and the rates of guest exchange decrease for larger cations. The higher activation barriers for in/out exchange of the larger guests suggest tight conformational restraints in the transition state. It is likely that complete dissociation of one resorcinarene molecule is necessary for the exchange of the alkylammonium salts.     

Encapsulation of small molecules by a cavitand porphyrin self-assembled via quadruple hydrogen bonds

A new and stable quadruple hydrogen-bonded capsule, tetracarboxylcavitand.meso-tetra(2-pyridyl)porphyrin (1 x 2) has been synthesized and spectroscopically characterized. 1 x 2 can encapsulate small molecules of various size from methane to cyclopentane. The guest and host exchange rates were evaluated by EXSY.     

Halogen‐Bonded Supramolecular Capsules in the Solid State,in Solution,and in the Gas Phase

Supramolecular capsules were assembled by neutral halogen bonding (XB) and studied in the solid state, in solution, and in the gas phase. The geometry of the highly organized capsules is shown by an X‐ray crystal structure which features the assembly of two XB hemispheres, geometrically rigidified by H‐bonding to eight MeOH molecules and encapsulation of two benzene guests. To enhance capsular association strength, tuning the XB donor is more efficient than tuning the XB acceptor, due to desolvation penalties in protic solvents, as shown for a tetraquinuclidine XB acceptor hemisphere. With a tetra(iodoethynyl) XB donor and a tetralutidine XB acceptor, the association in deuterated benzene/acetone/methanol 70:30:1 at 283 K reaches K _a=(2.11±0.39)×10⁵ m ⁻¹ (ΔG =−6.9±0.1 kcal mol⁻¹). The stability of the XB capsules in the gas phase was confirmed by electrospray ionization mass spectrometry (ESI‐MS). A new guest binding site was uncovered within the elongated iodoethynyl capsule.     

Chiral Encapsulation by Directional Interactions

The complexation of chiral guests in the cavity of dimeric self‐assembled chiral capsule 1 ₂ was studied by using NMR spectroscopy and X‐ray crystallography. Capsule 1 ₂ has walls composed of amino acid backbones forming numerous directional binding sites that are arranged in a chiral manner. The polar character of the interior dictates the encapsulation preferences towards hydrophilic guests and the ability of the capsule to extract guests from water into an organic phase. Chiral discrimination towards hydroxy acids was evaluated by using association constants and competition experiments, and moderate de values were observed (up to 59 %). Complexes with one or two guest molecules in the cavity were formed. For 1:1 complexes, solvent molecules are coencapsulated; this influences guest dynamics and makes the chiral recognition solvent dependent. Reversal of the preferences can be induced by coencapsulation of a nonchiral solvent in the chiral internal environment. For complexes with two guests, filling of the capsule’s internal space can be very effective and packing coefficients of up to 70 % can be reached. The X‐ray crystal structure of complex 1 ₂?((S) ‐6 )₂ with well‐resolved guest molecules reveals a recognition motif that is based on an extensive system of hydrogen bonds. The optimal arrangement of interactions with the alternating positively and negatively charged groups of the capsule’s walls is fulfilled by the guest carboxylic groups acting simultaneously as hydrogen‐bond donors and acceptors. An additional guest molecule interacting externally with the capsule reveals a possible entrance mechanism involving a polar gate. In solution, the structural features and dynamic behavior of the D₄‐symmetric homochiral capsule were analyzed by variable‐temperature NMR spectroscopy and the results were compared with those for the S₈‐symmetric heterochiral capsule.     

Making amines strong bases: thermodynamic stabilization of protonated guests in a highly-charged supramolecular host1

A highly charged, cavity-containing supramolecular assembly formed by metal-ligand interactions acts as a host to dramatically shift the effective basicity of encapsulated protonated amine guests. The scope of encapsulated protonated amine and phosphine guests shows size selectivity consistent with a constrained binding environment. Protonation of the encapsulated guests is confirmed by (31)P NMR studies, mass spectrometry studies, and the pH dependence of guest encapsulation. Rates of guest self-exchange were measured using the selective inversion recovery method and were found to correlate with the size rather than with the basicity of the guests. The activation parameters for guest self-exchange are consistent with the established mechanism for guest exchange. The binding constants of the protonated amines are then used to calculate the effective basicity of the encapsulated amines. Depending on the nature of the guest, shifts in the effective basicities of the encapsulated amines of up to 4.5 pK(a) units are observed, signifying a substantial stabilization of the protonated form of the guest molecule and effectively making phosphines and amines strong bases.     

Cationic gemini guests promote the efficient self-assembly of capsular entities in water at neutral pH

Abstract

The binding features of a sulfonato-calix[4]arene with pyridinium-based gemini guests have been investigated in water at physiological condition by NMR spectroscopy. Results provided converging evidence showing that guests having different size, shape and flexibility formed water-soluble homodimeric supramolecular capsules. The remarkably large encapsulation efficiency of the anionic calixarene host towards these bis(pyridinium) gemini guests results from the favourable combination of electrostatic and hydrophobic interactions. The introduction of short and rigid spacers between the two positively charged heads of the guest improves the efficiency of the capsule formation. The insertion of a substituent into the pyridinium ring of the guest dramatically affects both the association constants and the binding modes.     

Structural alteration of hybrid supramolecular capsule induced by guest encapsulation

Heterofunctionalized C(2v) symmetrical cavitand 1 with 4-pyridylethynyl and 3-carbamoylphenyl groups in alternating arrangement was designed and synthesized. A 1:1 mixture of the cavitand 1 and a cis-coordinated palladium(II) or platinum(II) complex self-assembled into a hybrid supramolecular capsule via both metal-ligand coordination bonds and hydrogen bonds. Formation of the capsular assembly was confirmed by NMR spectroscopy and mass spectrometry. The hybrid capsule encapsulated the appropriate guest, the molecular sizes of which fit the size of the capsular cavity. Structural alteration of the hybrid capsule was induced by the guest encapsulation. A C(2h) structure for the encapsulation complex was assigned by 2D NMR spectra analysis. Thermodynamic and kinetic properties of the guest encapsulation were investigated. The kinetics of in/out guest exchange was strongly influenced by hydrogen bonding in the hybrid capsule.     

Self-assembly dynamics of a cylindrical capsule monitored by fluorescence resonance energy transfer

The constituent cavitands of a cylindrical capsule were labeled with donor and acceptor fluorophores, and fluorescence resonance energy transfer (FRET) was employed as a tool to study the dynamics of self-assembly. When donor and acceptor dyes are present in the same capsular assembly, they are brought within 25 A of each other, a distance suitable for efficient energy transfer to occur between them. This allowed for the study of interacting species at nanomolar concentrations providing information unattainable from NMR experiments. The kinetic stability of the capsule in the presence of various guest molecules was investigated which revealed a range of more than 4 orders of magnitude in the rates of cylindrical capsule exchange. While the thermodynamic stability of the capsule generally dictates the self-assembly dynamics, it was discovered that longer rigid guests can impart a significant kinetic barrier to monomer exchange.     

The Crystalline Sponge Method in Water

The crystalline sponge method entails the elucidation of the (absolute) structure of molecules from a solution phase using single-crystal X-ray diffraction and eliminates the need for crystals of the target compound. An important limitation for the application of the crystalline sponge method is the instability of the available crystalline sponges that can act as host crystals. The host crystal that is most often used decomposes in protic or nucleophilic solvents, or when guest molecules with Lewis basic substituents are introduced. Here a new class of (water) stable host crystals based on f-block metals is disclosed. It can be shown that these hosts not only increase the scope of the crystalline sponge method to a wider array of solvents and guests, but that they can even be applied to aqueous solutions containing hydrophilic guest molecules, thereby extending the crystalline sponge method to the important field of water-based chemistry.     

Reactivity of N-nitrosoamides in confined spaces

The thermal rearrangement of several N-nitrosoamides was studied by ¹H NMR in the context of reversible encapsulation. The N-nitrosoamide guests were isolated from the bulk solvent in a hydrogen-bonded dimeric host capsule which prevented their rearrangement. The guests appear to be preserved in their ground state conformations by the pressure exerted by the host. The conformations of the free and bound N-nitrosoamides are of comparable relative energies as determined by DFT calculations.     

A Dynamic Hydrogen‐Bonded Azo‐Macrocycle for Precisely Photo‐Controlled Molecular Encapsulation and Release

A light‐responsive system constructed from hydrogen‐bonded azo‐macrocycles demonstrates precisely controlled propensity in molecular encapsulation and release process. A significant decrease in the size of the cavity is observed in the course of the E→Z photoisomerization based on the results from DFT calculations and traveling wave ion mobility mass spectrometry. These macrocyclic hosts exhibit a rare 2:1 host–guest stoichiometry and guest‐dependent slow or fast exchange on the NMR timescale. With the slow host–guest exchange and switchable shape change of the cavity, quantitative release and capture of bipyridinium guests is achieved with the maximum release of 68 %. This work underscores the importance of slow host–guest exchange on realizing accurate release of organic cations in a stepwise manner under light irradiation. The light‐responsive system established here could advance further design of novel photoresponsive molecular switches and mechanically interlocked molecules.     

Kinetic investigations of the process of encapsulation of small hydrocarbons into a cavitand-porphyrin

Exchange of guest molecules into capsule shaped host molecules is the most fundamental process in host-guest chemistry. Several examples of quantitative measurements of guest exchange rates have been reported. However, there have been no reports on the activation energies of these processes. A molecule known as cavitand-porphyrin (H2CP) has been reported to have a flexible host structure capable of facilitating moderate guest exchange rates suitable for kinetic measurements of the guest exchange process with 1H NMR. In this article, various kinetic and thermodynamic parameters related to the process of encapsulation of small hydrocarbons into H2CP in CDCl3 solution were determined by 2D exchange spectroscopy (EXSY): association and dissociation rate constants (k(ass) = 320 M-1 s-1, k(diss) = 1.4 s-1 for methane at 25 degrees C), the corresponding activation energies (E(a,ass) = 27 kJ.mol-1, E(a,diss) = 58 kJ.mol-1), and thermodynamic parameters for each process (DeltaG++(ass) = 59 kJ.mol-1, DeltaG++(diss) = 72 kJ.mol-1, DeltaH++(ass) = 25 kJ.mol-1, DeltaH++(diss) = 55 kJ.mol-1, DeltaS++(ass) = -113 J.K-1.mol-1, and DeltaH++(diss) = 58 J.K-1.mol-1 for methane). The thermodynamic parameters (DeltaG degrees = -13 kJ.mol-1, DeltaH degrees = -31 kJ.mol-1, DeltaS degrees = -60 J.K-1.mol-1 for methane) for this encapsulation equilibrium determined by EXSY were comparable to those for methane determined by 1D 1H NMR titration (DeltaG degrees = -11 kJ.mol-1, DeltaH degrees = -33 kJ.mol-1, DeltaS degrees = -75 J.K-1.mol-1 for methane). In addition, the structure of the methane encapsulation process was revealed by ab initio MO calculations. The activation energies for methane association/dissociation were estimated from MP2 calculations (E(a,ass) = 58.3 kJ.mol-1, E(a,diss) = 89.1 kJ.mol-1, and DeltaH degrees = -30.8 kJ.mol-1). These values are in accord with the experimentally determined values. The observed guest exchange rates and energies are compared with the corresponding values of various reported capsule-shaped hosts.     

Bent alkanes in a new thiourea-containing capsule

The synthesis of a cavitand featuring thiourea hydrogen bonding sites and its dimerization in the presence of suitable guests are reported. Dimerization creates a capsule host wider than the corresponding urea or imide structures, and longer alkanes can be accommodated. Specifically, n-C(15)H(32) is encapsulated, but this guest appears folded inside as deduced from NMR studies. Apparently, the plasticity of hydrogen bonds between thiourea groups allows a stable encapsulation complex to persist in solution even though the guest is contorted.