Frank Biedermann

Ultrahigh-Water-Content Supramolecular Hydrogels Exhibiting Multistimuli Responsiveness

Hydrogels are three-dimensional networked materials that are similar to soft biological tissues and have highly variable mechanical properties, making them increasingly important in a variety of biomedical and industrial applications. Herein we report the preparation of extremely high water content hydrogels (up to 99.7% water by weight) driven by strong host-guest complexation with cucurbit[8]uril (CB[8]). Cellulosic derivatives and commodity polymers such as poly(vinyl alcohol) were modified with strongly binding guests for CB[8] ternary complex formation (K(eq) = 10(12) M(-2)). When these polymers were mixed in the presence of CB[8], whereby the overall solid content was 90% cellulosic, a lightly colored, transparent hydrogel was formed instantaneously. The supramolecular nature of these hydrogels affords them with highly tunable mechanical properties, and the dynamics of the CB[8] ternary complex cross-links allows for rapid self-healing of the materials after damage caused by deformation. Moreover, these hydrogels display responsivity to a multitude of external stimuli, including temperature, chemical potential, and competing guests. These materials are easily processed, and the simplicity of their preparation, their availability from inexpensive renewable resources, and the tunability of their properties are distinguishing features for many important water-based applications.

The hydrophobic effect revisited--studies with supramolecular complexes imply high-energy water as a noncovalent driving force.

Traditional descriptions of the hydrophobic effect on the basis of entropic arguments or the calculation of solvent-occupied surfaces must be questioned in view of new results obtained with supramolecular complexes. In these studies, it was possible to separate hydrophobic from dispersive interactions, which are strongest in aqueous systems. Even very hydrophobic alkanes associate significantly only in cavities containing water molecules with an insufficient number of possible hydrogen bonds. The replacement of high-energy water in cavities by guest molecules is the essential enthalpic driving force for complexation, as borne out by data for complexes of cyclodextrins, cyclophanes, and cucurbiturils, for which complexation enthalpies of up to -100 kJ mol(-1) were reached for encapsulated alkyl residues. Water-box simulations were used to characterize the different contributions from high-energy water and enabled the calculation of the association free enthalpies for selected cucurbituril complexes to within a 10% deviation from experimental values. Cavities in artificial receptors are more apt to show the enthalpic effect of high-energy water than those in proteins or nucleic acids, because they bear fewer or no functional groups in the inner cavity to stabilize interior water molecules.

Strongly Fluorescent, Switchable Perylene Bis(diimide) Host–Guest Complexes with Cucurbit[8]uril In Water†

Supramolecular complexation of perylene bis(diimide) (PDI) dyes with the macrocyclic host cucurbit[8]uril (CB[8]) prevents self-aggregation of the dye molecules and enables their use as highly (photo)chemically stable, strongly-emitting fluorophores in water. The complexes are stimuli-responsive to binders and can be electrochemically cycled, leading to reversible on-off fluorescence switching and access to noncovalent formation of higher-order architectures in water.

Experimental Binding Energies in Supramolecular Complexes

On the basis of many literature measurements, a critical overview is given on essential noncovalent interactions in synthetic supramolecular complexes, accompanied by analyses with selected proteins. The methods, which can be applied to derive binding increments for single noncovalent interactions, start with the evaluation of consistency and additivity with a sufficiently large number of different host-guest complexes by applying linear free energy relations. Other strategies involve the use of double mutant cycles, of molecular balances, of dynamic combinatorial libraries, and of crystal structures. Promises and limitations of these strategies are discussed. Most of the analyses stem from solution studies, but a few also from gas phase. The empirically derived interactions are then presented on the basis of selected complexes with respect to ion pairing, hydrogen bonding, electrostatic contributions, halogen bonding, π-π-stacking, dispersive forces, cation-π and anion-π interactions, and contributions from the hydrophobic effect. Cooperativity in host-guest complexes as well as in self-assembly, and entropy factors are briefly highlighted. Tables with typical values for single noncovalent free energies and polarity parameters are in the Supporting Information.

Quantitative SERS using the sequestration of small molecules inside precise plasmonic nanoconstructs

We show how the macrocyclic host, cucurbit[8]uril (CB[8]), creates precise subnanometer junctions between gold nanoparticles while its cavity simultaneously traps small molecules; this enables their reproducible surface-enhanced Raman spectroscopy (SERS) detection. Explicit shifts in the SERS frequencies of CB[8] on complexation with guest molecules provides a direct strategy for absolute quantification of a range of molecules down to 10(-11) M levels. This provides a new analytical paradigm for quantitative SERS of small molecules.

Correlating solution binding and ESI-MS stabilities by incorporating solvation effects in a confined cucurbit[8]uril system.

The high-throughput characterization of solution binding equilibria is essential in biomedical research such as drug design as well as in material applications of synthetic systems in which reversible binding interactions play critical roles. Although isothermal titration calorimetry (ITC) has been widely employed for describing such binding events, factors such as speed, concentration, and sample complexity would principally favor a mass spectrometry approach. Here, we show a link between ITC and electrospray ionization mass spectrometry (ESI-MS) by incorporating solvation free energies in the study of the ternary complexes of the macrocyclic host cucurbit[8]uril (CB[8]). The binding affinities of 32 aromatic reference complexes were studied by ITC and ESI-MS and combined with solvation data of the guests from an implicit solvation model (SM8) to obtain a correlation between aqueous and gas-phase measurements. The data illustrates the critical importance of solvation on the binding strength in CB[8]s ternary complexes. Finally, this treatment enabled us to predict association constants that were in excellent agreement with measured values, including several highly insoluble guest compounds.

A supramolecular route for reversible protein-polymer conjugation

The supramolecular formation of a PEGylated bovine serum albumin (BSA) protein-polymer bio-conjugate in water has been demonstrated through a selective host–guest interaction with the macrocycle cucurbit[8]uril (CB[8]). Both BSA and poly(ethylene glycol) were functionalised with either an electron-deficient first guest viologen or an electron-rich second guest naphthalene for the formation of the CB[8] ternary complex. With the help of spectroscopic (NMR, DOSY-NMR, DLS, UV/vis, fluorescence) and calorimetric (ITC) techniques, it was shown that a strong and specific binding interaction took place between the complementary labeled polymer and protein only in the presence of the macrocyclic host CB[8]. Moreover, we demonstrated that controlled formation of a supramolecular protein-protein complex was also possible through the use of CB[8] ternary formation.

Benzobis(imidazolium)–Cucurbit[8]uril Complexes for Binding and Sensing Aromatic Compounds in Aqueous Solution

The utilities of benzobis(imidazolium) salts (BBIs) as stable and fluorescent components of supramolecular assemblies involving the macrocyclic host, cucurbit[8]uril (CB[8]), are described. CB[8] has the unusual ability to bind tightly and selectively to two different guests in aqueous media, typically methyl viologen (MV) as the first guest, followed by an indole, naphthalene, or catechol-containing second guest. Based on similar size, shape, and charge, tetramethyl benzobis(imidazolium) (MBBI) was identified as a potential alternative to MV that would increase the repertoire of guests for cucurbit[8]uril. Isothermal titration calorimetry (ITC) studies showed that MBBI binds to CB[8] in a 1:1 ratio with an equilibrium association constant (K(a)) value of 5.7×10(5) M(-1), and that the resulting MBBI·CB[8] complex binds to a series of aromatic second guests with K(a) values ranging from 10(3) to 10(5) M(-1). These complexation phenomena were supported by mass spectrometry, which confirmed complex formation, and a series of NMR studies that showed the expected upfield perturbation of aromatic peaks and of the MBBI methyl peaks. Surprisingly, the binding behavior of MBBI is strikingly similar to that of MV, and yet MBBI offers a number of substantial advantages for many applications, including intrinsic fluorescence, high chemical stability, and broad synthetic tunability. Indeed, the intense fluorescence emission of the MBBI·CB[8] complex was quenched upon binding to the second guests, thus demonstrating the utility of MBBI as a component for optical sensing. Building on these favorable properties, the MBBI·CB[8] system was successfully applied to the sequence-selective recognition of peptides as well as the controlled disassembly of polymer aggregates in water. These results broaden the available guests for the cucurbit[n]uril family and demonstrate potentially new applications.

Noncovalent Chirality Sensing Ensembles for the Detection and Reaction Monitoring of Amino Acids, Peptides, Proteins, and Aromatic Drugs

Ternary complexes between the macrocyclic host cucurbit[8]uril, dicationic dyes, and chiral aromatic analytes afford strong induced circular dichroism (ICD) signals in the near-UV and visible regions. This allows for chirality sensing and peptide-sequence recognition in water at low micromolar analyte concentrations. The reversible and noncovalent mode of binding ensures an immediate response to concentration changes, which allows the real-time monitoring of chemical reactions. The introduced supramolecular method is likely to find applications in bioanalytical chemistry, especially enzyme assays, for drug-related analytical applications, and for continuous monitoring of enantioselective reactions, particularly asymmetric catalysis.

A Systems Approach to Controlling Supramolecular Architecture and Emergent Solution Properties via Host−Guest Complexation in Water

The assembly behavior of aryl/alkyl imidazolium ionic liquid salts in aqueous solution has been investigated. These salts undergo self-assembly into one-dimensional stacks via hydrophobic and π-π interactions upon increasing concentration, which led to a substantial increase in the solution viscosity in water. Addition of the macrocyclic host molecules cucurbit[n]urils (CB[n]) were found to effectively alter the supramolecular assemblies, as evidenced from the dramatic increase (by CB[7]) and decrease (by CB[8]) in solution viscosity and aggregation size in water, on account of the different binding stoichiometries, 1:1 complexation with CB[7] and 2:1 complexation with CB[8]. Furthermore, the aggregate architectures were controllably modified by competitive guests for the CB[n] hosts. This complex supramolecular systems approach has tremendous implications in the fields of molecular sensor design, nonlinear viscosity modification, and controlled release of target molecules from a defined supramolecular scaffold in water.