In Search of Wasserman's Catenane.

We repeat the earliest claimed [2]catenane synthesis, reported by Wasserman over 60 years ago, in order to ascertain whether or not a nontemplate, statistical synthesis by acyloin macrocyclization does indeed form mechanically interlocked rings. The lack of direct experimental evidence for Wasserman's catenane has led to it being described as a "prophetic compound", a technical term used in patents for claimed molecules that have not yet been synthesized. Contemporary synthetic methods were used to reconstruct Wasserman's deuterium-labeled macrocycle and other building blocks on the 10-100 g reaction scale necessary to generate, in principle, ∼1 mg of catenane. Modern spectrometric and spectroscopic tools and chemical techniques (including tandem mass spectrometry, deuterium nuclear magnetic resonance (NMR) spectroscopy, and fluorescent tag labeling) were brought to bear in an effort to detect, isolate, and prove the structure of a putative [2]catenane consisting of a 34-membered cyclic hydrocarbon mechanically linked with a 34-membered cyclic α-hydroxyketone.

Stabilization of reactive species by supramolecular encapsulation.

Molecular containers have attracted the interest of supramolecular chemists since the early beginnings of the field. Cavitands' inner cavities were quickly exploited by Cram and Warmuth to construct covalent containers able to stabilize and assist the characterization of short-lived reactive species such as cyclobutadiene or o-benzyne. Since then, more complex molecular architectures have been prepared able to store and isolate a myriad of fleeting species (i.e. organometallic compounds, cationic species, radical initiators…). In this review we cover selected examples of the stabilization of reactive species by encapsulation in molecular containers from the first reports of covalent containers described by Cram et al. to the most recent examples of containers with self-assembled structure (metal coordination cages and hydrogen bonded capsules). Finally, we briefly review examples reported by Rebek et al. in which elusive reaction intermediates could be detected in the inner cavities of self-folding resorcin[4]arene cavitands by the formation of covalent host-guest complexes. The utilization of encapsulated reactive species in catalysis or synthesis is not covered.

Tetra-phosphonate calix[4]pyrrole cavitands as multitopic receptors for the recognition of ion pairs.

The synthesis, structural characterization, and binding properties of two unprecedented multitopic receptors for ion-pair recognition are described. We isolated two of the six possible diastereomeric deep cavitand receptors resulting from the installation of four phosphonate groups at the upper rim of a calix[4]pyrrole-resorcin[4]arene hybrid scaffold. The isolated tetra-phosphonate receptors display either three (iooo) or four (oooo) of their P═O groups oriented away from the deep and functionalized aromatic cavity. In contrast to analogous tetra-phosphonate resorcin[4]arene cavitands, the 14-membered macrocyclic rings that contain the P═O groups in the tetra-phosphonate calix[4]pyrrole cavitands are conformationally flexible, always adopting a conformation locating the phenyl substituents in equatorial position. The tetra-phosphonate calix[4]pyrroles exhibited larger affinity constants than the previously reported bis-phosphonate calix[4]pyrrole counterparts in the complexation of both tetramethylphosphonium and octylammonium chloride salts in nonpolar solvents. We demonstrated that the iooo diastereoisomer was able to function as a multitopic receptor for organic chloride salts by switching the geometry of the 1:1 ion-paired complex from receptor-separated to close-contact depending on the quaternary or primary nature of the cobound organic cation. The ion-paired 1:1 complexes formed between the diastereomeric receptors and organic chloride salts were studied and thermodynamically characterized in solution. The determined stability constant values were compared to those obtained for the bis-phosphonate counterparts. The structure of the TMPCl⊂7iooo complex was determined by X-ray structure, and its formation was also evidenced in the gas phase.

Synthesis, structure, and binding properties of lipophilic cavitands based on a calix[4]pyrrole-resorcinarene hybrid scaffold.

We report the synthesis, structural characterization, and binding properties of a series of unprecedented cavitands based on a meso-dodecyl-calix[4]pyrrole-resorcin[4]arene hybrid scaffold. The reported structural and conformational features of the prepared cavitands are derived from results obtained in solution, solid state, and molecular modeling studies. In the solid state, these cavitands are exclusively observed in the kite C4 structure and as a racemic mixture of two cyclochiral conformers, which are interconverting fast on the (1)H NMR time scale, according to solution studies. In agreement, molecular modeling studies assign an energy preference for the kite conformer of the cavitands. The polar interior of the synthesized containers allows for the inclusion of a series of pyridine N-oxide derivatives. This results in the formation of 1:1 complexes that are kinetically and thermodynamically highly stable. The putative switching process between the vase and kite forms of these cavitands is investigated in solution by means of variable temperature (1)H NMR experiments. N-Oxide guests that are size and shape complementary to the volume of the cavity of the vase form are also employed to facilitate its emergence. All of the results obtained indicate the existence of a remarkable preference toward the kite conformation both in free and bound calix[4]pyrrole-based cavitands.

Coaxial assembly of helical aromatic foldamers by metal coordination.

Deprotonation of acid-terminated helical aromatic foldamers with a mineral base in chlorinated solvents led to their dimerization through the coordination of a metal cation (Li+, Na+, K+, Ag+, or Hg2+) with the terminal carboxylate functions. This new ligation method was applied to oligomerize diacid-functionalized foldamers.

Template-directed self-assembly of dynamic covalent capsules with polar interiors.

Chiral polyimine molecular capsules with polar interiors have been prepared through template covalent dynamic self-assembly. An aryl-extended tetraaldehyde calix[4]pyrrole scaffold was condensed with suitable diamines as linkers using templates for efficient self-assembly. The capsular complexes were characterized in solution, gas phase and the solid-state. Unprecedented transfer of asymmetry was observed from a chiral diamine linker to the resulting supramolecular capsular assembly.

A chiral "Siamese-Twin" calix[4]pyrrole tetramer.

We describe our results in the attempted template syntheses of oligomacrocycle calix[4]pyrrole dimer 4, using Hay coupling reaction conditions, tetraalkynyl calix[4]pyrrole 5 as starting material and two bipyridyl N-oxides of different length as templates. We found that the short bis-N-oxide 3 was not an efficient template for the macrocyclization reaction producing an insoluble crude reaction mixture containing exclusively oligomerization and polycondensation products. On the other hand, when we used the long bis-N-oxide 6 as template we obtained a soluble crude reaction mixture in which we did not detect the expected calix[4]pyrrole dimer 4. Instead, we isolated, in low yield, an encapsulation complex of the bis-N-oxide 6 in a partially reacted calix[4]pyrrole dimer. The major isolated species was an unprecedented calix[4]pyrrole tetramer encapsulating two molecules of 6. The complex adopted a chiral helical-like conformation in the solid state resembling the previously described so-called "Siamese-Twin porphyrins".

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.

Ordered co-encapsulation of chloride with polar neutral guests in a tetraurea calix[4]pyrrole dimeric capsule.

In this work, we describe the stoichiometrically controlled self-assembly process of tetraurea calix[4]pyrrole 1 with a polar neutral guest, trimethylamine N-oxide or beta-alanine betaine, and methyltrioctylammonium chloride (MTOACl) salt into two supramolecular architectures which differ in morphology and stoichiometry. Whereas an equimolar solution of tetraurea calixpyrrole 1, polar guest and MTOACl produces a four-particle inclusion assembly, a mixture of the same components in a 2 : 1 : 1 molar ratio induces the formation of a dimeric capsular assembly displaying multiple guests which are orderly co-encapsulated. The influence of other polar guests and ammonium salts on the self-assembly process is also described.

Kinetic stabilization of N,N-dimethyl-2-propyn-1-amine N-oxide by encapsulation.

Thermally and in nonprotic media N,N-dimethyl-2-propyn-1-amine N-oxide undergoes two consecutive sigmatropic rearrangements affording propenal. Two molecular containers capable of the quantitative inclusion/encapsulation of the N-oxide are described. The N-oxide becomes kinetically stabilized when included in the containers. The relationship between the observed kinetic stabilization of the N-oxide and the thermodynamic and kinetic stability of its inclusion complexes is explained and modeled.