Franz P. Schmidtchen

A new triazole-strapped calix[4]pyrrole synthesised via ‘click’ chemistry shows high affinity for chloride and lipid bilayer chloride transport properties.

Calix[4]pyrrole–chloride interactions are affected not only by the choice of countercation in halogenated solvents, but show a specific dependence on the way in which these cations are bound within the electron rich, bowl‐like calix[4]pyrrole cavity formed upon chloride anion complexation. In dichloromethane, the affinities of simple meso‐octamethylcalix[4]pyrrole (1) for methyl‐, ethyl‐, and n‐butylammonium chlorides are on the order of 10⁵, 10⁴, and 10² M⁻¹, respectively, as determined from isothermal titration calorimetry (ITC) analyses. These cation‐dependent anion affinity effects, while clearly evident, are less pronounced in other halogenated solvents, such as 1,2‐dichloroethane. Support for the proposed cation complexation selectivity is provided by solid state X‐ray crystallographic analyses.

The bicyclic hexahydropyrimidino[1,2a]pyrimidine cationic scaffold has a well-known capacity to bind a variety of oxoanions (phosphates, carboxylates, squarates, phosphinates). Based on this feature, the parent host was supplemented with sec-carboxamido substituents to generate compounds 1–3 in an effort to improve the anion-binding affinity and selectivity and to learn about the role and magnitude of entropic factors. Bicyclic guanidinium compounds were prepared by a convergent strategy via the corresponding tetraester 22 followed by catalytic amidation. Host–guest binding studies with isothermal titration calorimetry in acetonitrile probed the behavior of artificial hosts 1–3 in comparison with the tetraallylguanidinium compound 4 on binding p-nitrobenzoate, dihydrogenphosphate, and 2,2′-bisphenolcyclophosphate guests that showed enhanced affinities in the 10⁵–10⁶ M⁻¹ range. Contrary to expectation, better binding emerges from more positive association entropies rather than from stronger enthalpic interactions (hydrogen bonding). In an NMR spectroscopy titration in DMSO, o-phthalate was sufficiently basic to abstract a proton from the guanidinium function, as confirmed by an X-ray crystal structure of the product. The novel carboxamide-appended anchor groups also bind carboxylates and phosphates, but not hydrogen sulfate in methanol with affinities in excess of 10⁴ M⁻¹. The energetic signature of the complexation in methanol is inverted with respect to acetonitrile solvent and shows a pattern of general ion pairing with strong positive entropies overcompensating endothermic binding enthalpies. This study provides an example of the fact that bona fide decoration of a parent guanidinium anchor function with an additional binding functionality may provide the desired enhancement of the host–guest affinity, yet for a different reason than that implemented by design as guided by standard molecular modeling.

With the goal to improve host–guest binding affinity, while retaining guest selectivity, the parent calixpyrrole artificial receptor unit was decorated with four sulfonium moieties (e.g.3b) placed rigidly in symmetrical fashion remote from the core binding site. The determination of binding constants using isothermal titration calorimetry (ITC), in conjunction with trend analyses in a series of related anions, reveals the occurrence of several specific and unspecific binding steps. The former predominate in affinity by 20–1000 fold depending on guest charge and structure. The dissection of the free energy of association into its enthalpic and entropic parts, in combination with structural variation in the guest anion, offers insight into the nature and diversity of the guest binding modes. On these grounds, the supplementation of parent host scaffolds with rigidly positioned positive charge centers, holds promise as a general concept for anion binding in competitive media.

The interaction of calixpyrrole with several chloride salts has been studied in the solid state by X-ray crystallography as well as in solution by isothermal titration calorimetry (ITC) and ¹H NMR spectroscopic titrations. The titration results in dimethylsulfoxide, acetonitrile, nitromethane, 1,2-dichloroethane, and dichloromethane, carried out using various chloride salts, specifically tetraethylammonium (TEA), tetrapropylammonium (TPA), tetrabutylammonium (TBA), tetraethylphosphonium (TEP), tetrabutylphosphonium (TBP), and tetraphenylphosphonium (TPhP), showed no dependence on method of measurement. The resulting affinity constants (K_a), on the other hand, were found to be highly dependent on the choice of solvent with K_a's ranging from 10²−10⁵ M^-1 being recorded in the test solvents used for this study. In dichloromethane, a strong dependence on the countercation was also seen, with the K_a's for the interaction with chloride ranging from 10²−10⁴ M^-1. In the case of TPA, TBA, and TBP, the ITC data could not be fit to a 1:1 binding profile.

An attempt to experimentally estimate the role of binding‐mode diversity (structural fuzziness) on the molecular recognition seen in the prominent guanidinium–oxoanion host–guest pair is described. The global heat response as measured by isothermal titration calorimetry in acetonitrile, which was obtained from the interaction of five different but structurally closely related guanidinium hosts with three rigid phosphinate guests of decreasing accessibility of their binding sites, is correlated to provide a trend analysis. All host–guest associations of 1:1 stoichiometry in this series are strongly enthalpy‐driven. The change in complexation entropy can be related to the tightness of the mutual fit of the host–guest partners, which approaches a minimum limit and is interpreted as the unique lock‐and‐key binding mode. The ordinary host–guest complexation in this ensemble features substantial positive entropy changes that correlate inversely with the binding interface area. This finding excludes desolvation effects as the major cause of entropy production, and provides evidence for the existence of a broad variety of complex configurations rather than a single binding mode to represent the associated host–guest pair. This result bears on the molecular design of systems that vitally depend on structural fidelity, such as nanoassemblies or homogeneous catalysis.

The molecular recognition of both camphor enantiomers 2 with the chiral α-cyclodextrin (α-CD) 1 in water and D₂O was examined by calorimetry. On the basis of statistically supported determinations the thermodynamics of 2:1 host–guest binding and chiral discrimination was evaluated. The energetic signature strongly supports hydrophobic interaction as the dominant driving force for camphor encapsulation by α-CD in water. The solvent isotope effect on the binding equilibrium served to dissect the experimental enthalpy ΔH_ass into direct interaction (ΔH_intr) and solvent reorganization (ΔH_solv) terms. From this analysis the mutual interaction of two cyclodextrin and one camphor molecules contributes only 25 % to the observed enthalpy of binding ΔH_ass, all the rest is attributed to solvent restructuring. Furthermore, the dramatic change in the pattern of thermodynamic state functions on solvent transfer from water to D₂O is taken as compeling evidence for the involvement of water as a structural tectone in the supramolecular architecture of the 2:1 complex. As a corollary, bilateral host–guest interactions as conveyed by the lock-and-key metaphor of molecular recognition provide an inadequate description of this seemingly simple artificial host–guest system.