Extended covalent containers: synthesis and guest encapsulation.

The synthesis and characterization of two new covalent capsules are described. The structures use biphenyl and azobenzene spacers capped on both ends with deep cavitands. The tubular capsules are robust in a range of media and accommodate guests as long as squalene.

Effect of galnon on induction of long-term potentiation in dentate gyrus of C57BL/6 mice.

The impairment of cognitive performance by galanin administration in rodents indicates a possible modulating effect of this neuropeptide on long-term potentiation (LTP) induction in the hippocampal formation. Galnon is a non-peptide, systemically active galanin receptor agonist which has been tested in feeding, seizure and forced swim task in in vivo rodent experimental models. Similarly to galanin (1-29) (i.c.v.), galnon (i.p.) has exhibited anticonvulsant effects in rats. We have investigated the effect of galnon on the synaptic transmission and plasticity in hippocampal dentate gyrus (DG) of C57Bl/6 mice and compared the galnon effects to the effect of galanin (1-29) and galmic, a non-peptide galanin receptor agonist. Similarly to galanin (1-29) and galmic, superfusion of galnon did not alter the input-output responses in DG. Administration of galnon (1 microM) significantly attenuated the LTP induction by 85.5 +/- 1% by 51 min after high frequency trains stimulation. This result was very similar to the effect of galanin (1-29) and galmic, which caused an 80 +/- 1.5% and 94 +/- 2% reduction in the level of field potentiation, respectively. The PPF responses, however, were not altered due to galnon superfusion which is in contrast to the effect of galanin (1-29) or galmic. In summary, these data indicate that the systemically active, non-peptide galanin receptor agonist, galnon can exert similar effects to galanin (1-29) in attenuation of DG LTP in mice.

"Flexiball" toolkit: a modular approach to self-assembling capsules.

We report the synthesis and characterization of new, self-assembling molecular capsules. The modular strategy makes use of glycoluril building blocks available in multigram amounts combined with aromatic spacer elements. The lengthy syntheses encountered with earlier generations of capsules are avoided, and several capsules of nanometer dimensions are now accessible. Single bond attachments between spacers and glycoluril modules result in monomers as dimeric capsules that are less rigid than their earlier counterparts. The host-guest properties of the homo- and heterodimeric capsules were studied using a combination of NMR and ESI-mass spectrometry. They show a less pronounced selectivity for guests of different sizes, and their increased flexibility prevents self-assembly when no rigidifying elements are present on the central spacer unit. Some of the new capsules bear inwardly directed, secondary amide N-H protons. These can be further functionalized, as shown by their methylation to give tertiary analogues. The structures hold broader implications for the placement of functional groups on concave molecular surfaces.

A self-folding metallocavitand.

The synthesis and characterization of novel metallocavitand 6 are described. This is a covalent hybrid of a deepened, self-folding cavity and a Zn-phenanthroline fragment. Host 6 features a large molecular cavity of approximately 8 x 10 A dimensions, and the metal binding site is directed in toward the cavity. Binding abilities of the metallocavitand in solution was demonstrated for quinuclidine 11 and Dabco 12 using UV-vis and 1H NMR spectroscopy. Intramolecular hydrogen bonds at the upper rims of cavitand 6 resist the unfolding of the inner cavities and thereby increase the energetic barrier to guest exchange. The exchange is slow on the NMR time scale (at ambient temperatures, CD2Cl2), and kinetically stable complexes result. Both the polyaromatic cavity and metallosite participate simultaneously in the binding event. Zinc-containing deep cavities may be attractive as catalytic chambers for hydrolysis and esterification.

Cavitand-porphyrins.

The synthesis and characterization of new nanoscale container molecules 7 and 8 are described. They are covalent hybrids of deepened, self-folding cavitands and metalloporphyrins. In receptor 7, the Zn-porphyrin wall is directly built onto the cavitand skeleton. Host 8 features a large unimolecular cavity containing two cavitands attached with the Zn-porphyrin wall. Its dimensions, approximately 10 x 25 A, place it among the largest synthetic hosts prepared to date. A series of adamantyl- and pyridyl-containing guests 14-20 of various lengths were prepared and used to determine the hosts' binding abilities in solution using UV/vis and (1)H NMR spectroscopy. Intramolecular hydrogen bonds at the upper rims of the cavitands resist the unfolding of the inner cavities and thereby increase the energetic barrier to guest exchange. The exchange is slow on the NMR time scale (at < or =300 K), and kinetically stable complexes result. When the cavities and metalloporphyrins participate simultaneously in the binding event, very high affinities for guests are found (-DeltaG295 up to 10 kcal x mol(-1) in toluene), to which the porphyrin fragments contribute significantly (-DeltaG295 up to 6 kcal x mol(-1)). The pairwise selection of two different guests by molecular container 8 is reported, and the termolecular complex formed raises the possibility of metal-catalyzed bimolecular reactions in these containers.

Chiral softballs: synthesis and molecular recognition properties.

Studies on the different congeners of the softball were undertaken to explore structural variants for enantioselective encapsulation. Two different spacer elements in the monomeric subunit render the dimeric softball chiral although the monomer itself is achiral. The dimers represent capsules with dissymmetric cavities with volumes ranging from 190 to 390 A(3). The cavities are distorted spheres, and asymmetric guests, such as naturally occurring terpenes, generally prefer one enantiomer of the capsule to its mirror image. The selectivities are moderate (up to 4:1). The complexation studies show that the host capsules are flexible enough to arrange themselves comfortably around a guest but still maintain enough rigidity to be influenced by the occupancy of a chiral guest. The enantiomeric capsules can interconvert (racemize) by dissociation and recombination of their subunits.

Synthesis and applications of a deep, asymmetric cavitand on a solid support.

The synthesis of an optically active cavitand and its attachment to a polystyrene support are described. The cavitand is used for selective recognition based on size and shape of guest molecules in solution.

Reversible encapsulation by self-assembling resorcinarene subunits.

Encapsulation complexes are assemblies in which a reversibly formed host more or less completely surrounds guest molecules. Host structures held together by hydrogen bonds have lifetimes in organic solvents of milliseconds to hours, long enough to directly observe the encapsulated guest by NMR spectroscopy. We describe here the action of alkyl ammonium compounds as guests that gather up to six molecules of the host module to form encapsulation complexes. The stoichiometry of the complexes--the largest hydrogen-bonded host capsules to date--is determined by the size and concentration of the guest.

Reversible encapsulation of multiple, neutral guests in hexameric resorcinarene hosts.

A variety of aromatic guest molecules are co-encapsulated with Bu4SbBr in an assembly of six resorcinarene subunits.

Hydrogen-bonded capsules in polar, protic solvents.

A kinetically stable, dimeric capsule is formed by tetrahydroxyresorcinarene in methanol; it encapsulates tropylium and tetramethylammonium cations.

Highly selective synthesis of heterosubstituted aromatic sulfamides.

The sulfamide functional group is increasingly relevant in both medicinal and supramolecular chemistry, yet few selective synthetic steps are available for its elaboration. We report here a mild, general, and efficient method for the selective differentiation of N-atom substituents of aromatic sulfamides. [reaction: see text]

Emergent mechanical properties of self-assembled polymeric capsules.

Synthetic self-assembled systems combine responsiveness and reversibility with the ability to perform chemical tasks such as molecular recognition and catalysis. An unmet challenge is the construction of polymeric materials that, like nature's tubulin, are simultaneously reversible and capable of useful physical tasks. We report here a class of reversibly formed polymers that show covalent-polymer mechanical integrity in solution and in the solid state. Non-Newtonian, polymeric behavior is observed despite the low molecular weight of the individual subunits and the seemingly weak forces holding the assemblies together. These polymers assemble through self-complementary hydrogen bonding and by physical encapsulation of small molecules; accordingly, the emergent macroscopic structure and function can be controlled by appropriate chemical signals.

Hydrogen-bonding effects in calix

The synthesis and spectroscopic characterization of self-assembling calix[4]arene based capsules 1a.1a and 1b.1b are described. These compounds feature four urea substituents at the upper rims and four secondary amide fragments at the lower rims that can participate in inter- and intramolecular hydrogen bonding in apolar solution. Communication between the calixarene rims in 1a, b influences the self-assembled cavity's size and shape. Specifically. dimerization results in a perfect cone conformation of the calixarene skeleton in 1a, b and stabilizes a seam of intramolecular amide C=O...H-N hydrogen bonds at the lower rim. This seam is cycloenantiomeric, with either clockwise or counterclockwise arrangements of the head-to-tail amides. Complexation of Na+-cation breaks hydrogen bonds at the lower rim but maintains the capsular assembly. Encapsulation properties of 1a.1a and 1b.1b were studied in nonpolar solvents and their binary mixtures as well as through heterodimerization experiments. The presence of amide groups at the lower rim causes notable differences in the capsule's binding affinities when compared to the corresponding tetraester capsules 1c.1c and 1d.1d. In the monomeric state calixarenes 1a, b are in a pinched cone conformation. The solid state X-ray crystallographic studies with monomeric 1a reveal only two intramolecular C=O...H-N hydrogen bonds between the adjacent amides at the lower rim, and an extensive network of intermolecular hydrogen bonds between urea groups at the upper rim.

Induced-fit molecular recognition with water-soluble cavitands

Synthesis of novel water-soluble cavitands 1 and 2 and their complexes--the caviplexes--is described. The solubility in water derives from four primary ammonium groups on the lower rim and eight secondary amide groups on the upper rim. Cavitands 1 and 2 exist as D2d velcraplex dimers in aqueous solution but the addition of lipophilic guests 15-24 induces conformational changes to the vase-like structures. The internal cavity dimensions are 8 x 10 A, and the exchange rates of guests in the caviplexes are slow on the NMR time-scale (room temperature and 600 MHz). The direct observation of bound species and the stoichiometry of the complexes is reported. The association constants (Ka) between 0.4 x 10(-1) (-deltaG295= 0.7 kcalmol(-1)) and 1.4 x 10(2)M(-1) (-deltaG295=2.9 kcalmol(-1)) in D2O and 1.4 x 10(1)(-deltaG295= 1.7 kcalmol(-1)) and 2.8 x 10(4)M(-1)(-deltaG295=6.0 kcalmol(-1)) in [D4]methanol for aliphatic guests 16-24 were determined. Guest exchange rates of the new hosts 1 and 2 are considerably slower than rates observed for typical open-ended cavities in aqueous solution.

A polymer-bound cavitand.

[reaction: see text] An amino-footed cavitand, 1, was attached to an insoluble polystyrene support, and the uptake of organic guest molecules by the resulting polymer 3 from xylene or toluene solutions was achieved.

A cavitand-porphyrin hybrid.

[structure: see text] Host-guest complexes of a new open-ended cavitand show unprecedented stabilities. Simultaneous binding in the cavity and at the metalloporphyrin affects both the kinetics and the thermodynamics of caviplex formation.

Velcrands with snaps and their conformational control

A novel class of self-folding velcrands was prepared that dimerize through intermolecular forces. Solvophobic interactions on extended pi surfaces stabilize the dimer similar to velcrands, while eight hydrogen bonds act like snaps to hold the molecules together. The self-complementary array of hydrogen bonding sites were incorporated on the upper rim of a resorcinarene-based cavitand. A dramatic reorganization of shape and size of the internal cavity was manifested through changes in solvent polarity. Specifically, the equilibrium between the extended surface (D2d symmetry) and a deep cavity (C4v symmetry) could be manipulated in mixtures of aromatic solvents (or CDCl3) and [D6]DMSO. The switching of conformations and the dimerization motif are well-suited for the assembly of noncovalent polymeric materials.

A self-assembled cylindrical capsule: new supramolecular phenomena through encapsulation.

The synthesis and spectroscopic characterization of self-assembled cylindrical capsule 1a x 1a of nanometer dimensions is described. Encapsulation studies of large organic guest molecules were performed by using 1H NMR sprectroscopy in [D12]mesitylene solution. In addition to the computational (MacroModel 5.5, Amber* force field) analysis of the capsule's shape and geometry, an experimental approach towards estimation of the internal cavity dimensions is described. This involves using series of homologous molecular "rulers" (e.g. aromatic amides 5a-i). The available space inside the capsule 1a x 1a can be estimated as 5.7 x 14.7 A (error +/- 0.2 A) with this technique. Dibenzoyl peroxide is readily encapsulated in [D12]mesitylene and was shown to be stable to decomposition for at least three days at 70 degrees C inside the capsule. Moreover, 1a x 1a prevents the encapsulated peroxide from oxidizing Ph3P or diphenyl carbazide present in solution. The normal chemical reactivity of the peroxide is restored by release from the capsule by DMF, a solvent that competes for the hydrogen bonds that hold the capsule together. The protection and release of encapsulated species augurs well for the application of capsules in catalysis and delivery.

Guest exchange in an encapsulation complex: a supramolecular substitution reaction.

Encapsulation complexes are reversibly formed assemblies in which small molecule guests are completely surrounded by large molecule hosts. The assemblies are held together by weak intermolecular forces and are dynamic: they form and dissipate on time scales ranging from milliseconds to days-long enough for many interactions, even reactions, to take place within them. Little information is available on the exchange process, how guests get in and out of these complexes. Here we report that these events can be slow enough for conventional kinetic studies, and reactive intermediates can be detected. Guest exchange has much in common with familiar chemical substitution reactions, but differs in some respects: no covalent bonds are made or broken, the substrate is an assembly rather than a single molecule, and at least four molecules are involved in multiple rate-determining steps.