Kaisa Helttunen

Self-assembly of amphiphilic calixarenes and resorcinarenes in water

The calixarenes and resorcinarenes are macrocyclic phenolic molecules that can be modified “a facon” and a wide range of chemical modification strategies have been published over the last 30 years. Because of their remarkable structural properties and their relative ease of chemical modification, they represent excellent and highly versatile bases to design complex building blocks capable of self-assembly and molecular recognition. They have been widely studied for their ability to form supramolecular structures targeting a wide range of applications. The possibility to regio(rim)-selectively modify these macrocycles with different polar and apolar moieties provides synthetic chemists with an unlimited range of possibilities for the design of complex amphiphiles with a high control over the position of the grafted moieties in the three dimensions. These amphiphiles have been shown to possess outstanding self-assembling and/or molecular recognition properties. This short review describes the developments of the chemistry of amphiphilic calixarenes and resorcinarenes with a clear focus on the synthetic paths used for their production and their self-assembly properties in water.

Cation binding resorcinarene bis-crowns: the effect of lower rim alkyl chain length on crystal packing and solid lipid nanoparticles

A group of seven resorcinarene bis-crown ethers (CNBC5) with two polyether bridges at the upper rim and either propyl, butyl, pentyl, heptyl, nonyl, decyl or undecyl groups at the lower rim were synthesized and their binding properties with Cs+ were investigated by NMR titration. The bis-crowns form 1 : 2 complexes with Cs+ with binding constants of log K 4–5. Crystal structures of bis-crowns and their Cs+ and K+ complexes were studied and different packing motifs were found depending on the alkyl chain length. Short ethyl, propyl and butyl alkyl chains gave a layer or pillar packing where the polar and non-polar regions cannot be distinguished, whereas longer pentyl and decyl chains formed bilayers. Amphiphilic properties and self-assembly in water were studied by preparing solid lipid nanoparticles (SLNs) from the bis-crowns. All investigated compounds formed stable SLNs showing amphiphilic character, which in the case of the short chain bis-crowns probably arises from their locked boat conformation separating the polar face of the molecule from the non-polar face.

Interaction of aminomethylated resorcinarenes with rhodamine B

The interaction of aminomethylated resorcinarenes with a red xanthene dye, rhodamine B, was investigated in chloroform, methanol and chloroform–methanol solutions using UV-vis, NMR and fluorescence spectroscopy. Aminomethylated resorcinarenes 1 and 2 shift the rhodamine B equilibrium from the zwitterion to the lactone form unlike reference compounds 3 and 4, which do not contain tertiary amino groups at the upper rim, giving an example of how supramolecular hosts can influence the equilibrium of rhodamine B isomers.

Solid lipid nanoparticles from amphiphilic calixpyrroles

HYPOTHESIS Macrocyclic amphiphiles form interesting self-assembling structures, including solid lipid nanoparticles, which have potential applications in drug encapsulation. Aryl-extended calixpyrroles, which act as anion binding hosts, are expected to form solid lipid nanoparticles, even though the alkyl chains have unusual perpendicular geometry with respect to the hydrophilic head group. The preparation conditions and the alkyl chain length should affect the size and stability of the particles. EXPERIMENTS Solid lipid nanoparticles of two aryl-extended calixpyrroles with resorcinol walls and either meso-dodecyl or meso-methyl alkyl chains were compared. Ethanolic solutions of the calixpyrroles were mixed with water and the resulting nanoparticle dispersions were studied with dynamic light scattering and nanoparticle tracking analysis. The effect of different calixpyrrole/ethanol/water ratios on particle size was tested. The surface charge of the particles at different pH and NaCl concentration was determined by zeta potential measurements. FINDINGS The meso-dodecyl calixpyrrole produced small nanoparticles with mean hydrodynamic diameters between 40 and 70nm in 0.86-4.28M ethanol. The particles were stable in solution for several months. Particles prepared from meso-methyl calixpyrrole were larger and less stable. The smallest particles were obtained with low calixpyrrole concentration and calixpyrrole/ethanol ratio. Larger ethanol/water ratio induced broader particle size distributions. Increasing pH aided the stability of the particles due to increased negative surface charge.

Structural analysis of two foldamer-type oligoamides – the effect of hydrogen bonding on solvate formation, crystal structures and molecular conformation

The crystal structures and molecular conformations of two foldamer-type oligoamides were analyzed. One polymorphic form and seven solvates were found for N1,N3-bis(2-benzamidophenyl)benzene-1,3-dicarboxamide (the benzene variant), and two polymorphic forms and six solvates for N2,N6-bis(2-benzamidophenyl)pyridine-2,6-dicarboxamide (the pyridine variant). Three crystal structures of the benzene variant and seven structures of the pyridine variant were solved using single crystal X-ray diffraction. The crystal structures showed that the different modes of intramolecular hydrogen bonding strongly affect the conformation and folding of the molecules, which is most evidently seen with the strongly folded helical structure of the pyridine variant. NOESY experiments suggest that the intramolecular hydrogen bonding is stable enough to retain a folded or partially folded conformation even in solution.

Influence of lower rim C-methyl group on crystal forms and metal complexation of resorcinarene bis-crown-5

C-Methyl resorcinarene bis-crown-5 (1) with pendant methyl groups at the lower rim was prepared and crystallized in various solvent mixtures with and without selected metal salts. The crystal structures of two polymorphic forms of unsolvated 1 (1-I and 1-II), three solvates (acetonitrile, chloroform and dichloromethane–methanol), and three metal complexes with silver and cesium salts were obtained. The lower rim methyl groups and the block shape of the host promote crystal packing in brick-wall type assemblies, in which the binding cavities are efficiently filled by the crown bridges. Thus, solvents are found in the interstitial space or coordinated to the crown bridges on top of the cavity, whereas more strongly binding metal cations are able to occupy the cavity. The chloroform solvate proved to be a relatively labile crystal form, which transformed to unsolvated form (1-I) over time. Resorcinarene mono-crown-5 (2) was obtained as a minor product of the bridging reaction. Two solvate structures (acetonitrile and chloroform–water) of 2 are also reported, providing an example of the effect of the missing crown bridge on the solvate structures.

Supramolecular chirality and symmetry breaking of fluoride complexes of achiral foldamers

Aromatic oligoamide foldamers containing a central pyridine-2,6-dicarbonyl motif are partially preorganized to favor the binding of fluoride anions. In the solid state, the foldamer-fluoride complexes form achiral, polar and chiral crystal structures depending on the chemical structure of the foldamer. One of the six foldamers studied here, a C2v symmetrical foldamer (1), formed repeatedly chiral crystal structures when crystallized with tetra-butylammonium fluoride, showing supramolecular bulk chirality and symmetry breaking in crystallization.

Inverted molecular cups: 1-D and 2-D Ag(I) coordination polymers from resorcinarene bis-thiacrowns

Resorcinarene bis-thiacrown hosts 1–3 were prepared and crystallized with silver trifluoroacetate yielding one and two dimensional Ag coordination polymers. The complexation of silver in exo-cavity fashion folds the thiacrown bridges inwards transforming the resorcinarene hosts into inverted molecular cups. The silver cations were coordinated to the resorcinarene ligands and trifluoroacetate anions, which act as monodentate or bidendate bridging ligands between the metal ions. Argentophilic Ag⋯Ag (2.93–3.38 A) interactions supported by two bridging carboxylate anions were found in two of the structures, whereas longer Ag⋯Ag distances were observed if only one anion connected the silver cations. Both the anion and the resorcinarene lower rim alkyl chain had a role in the crystal packing, as indicated by the different metal coordination and packing tendencies of C-ethyl and C-pentyl bis-thiacrowns. A typical packing motif observed was a polymer chain with end-to-end joints and two Ag ions with tetrahedral coordination geometries. Solvent channels or discrete solvent pockets between the polymer layers were observed in all structures.

CCDC 1523875: Experimental Crystal Structure Determination

UDARID : ethyl N-benzoylalaninate Space Group: P212121, Cell: a 5.2938(2)A b 12.1920(8)A c 17.7130(4)A, α 90° β 90° γ 90° Work published 2017 via Cambridge Crystallographic Data Centre.

CCDC 1524052: Experimental Crystal Structure Determination

UDAKOC : diaqua-(μ-1,13-dioxa-4,7,10,16,19,22-hexaazacyclotetracosane)-bis(perchlorato)-di-copper(ii) diperchlorate tetrahydrate Space Group: P21/c, Cell: a 11.8763(3)A b 13.9146(4)A c 13.4024(4)A, α 90.00° β 123.439(2)° γ 90.00° Work published 2017 via Cambridge Crystallographic Data Centre.