Towards Amplified Probing of Weak Intermolecular Interactions on the External Surfaces of Molecular Capsules.

We report a sensitive method for comparing weak interactions between aryl rings located on the external surfaces of equilibrating homo- and heterodimeric capsules. Two identical self-complementary resorcin[4]arene tetrabenzoate molecules and one tetramethylammonium cation form in CDCl3 hydrogen-bonded homodimeric capsules whose exteriors are decorated with four tight pairs of weakly interacting aryl rings. The pair wise mixing of six different homodimers establishes their equilibria with the corresponding heterodimeric species in which two types of aryl rings exert on each other some gentle forces. This equilibrium is significantly shifted either towards homo- or heterodimers depending on the nature and location of the substituents in the weakly interacting aryl rings. The thermodynamic favorability or disadvantage of the heterodimerization is determined by stronger or weaker aryl-aryl attractions in the hetero- or homodimeric capsules, respectively. The four-fold amplification of weak aryl-aryl interactions on the external surfaces of the equilibrating capsules is responsible for high sensitiveness of our approach.

Combinatorial synthesis of chemical building blocks 1. Azomethines.

128 Azomethines were synthesized through condensation of carbonyl compounds with various amines in pyridine in the presence of Me(3)SiCl as promoter and water scavenger in 58-98 % yield. Et(3)N was added to reaction mixtures before precipitating the product with H(2)O to prevent acid catalyzed hydrolysis of the C=N bond. The scope and limitation of the method are discussed. High yields and simple setup/workup procedure make this method suitable for the combinatorial synthesis of azomethines, which are suitable as starting materials for high throughput synthesis of various combinatorial libraries. The azomethines synthesized were used as starting materials in a one-pot combinatorial synthesis of amines and amides.

High throughput synthesis of extended pyrazolo[3,4-d]dihydropyrimidines.

Thirteen 5-hetarylaminopyrazoles were synthesized in 62-93% yield through the arylation of 1-isopropyl- and 1-phenyl-5-aminopyrazoles with electrophilic hetarylhalides under optimized conditions. Condensation of 5-hetarylaminopyrazoles with carbonyl compounds facilitated by AcOH or Me(3)SiCl furnished 23 pyrazolo[3,4-d]dihydropyrimidines in 69-86% yield. The target compounds were isolated through simple crystallization. The scope and limitation of the method are discussed.

Drug- and lead-likeness, target class, and molecular diversity analysis of 7.9 million commercially available organic compounds provided by 29 suppliers.

A database of 7.9 million compounds commercially available from 29 suppliers in 2008-2009 was assembled and analyzed. 5.2 million structures of this database were identified to be unique and were subjected to an assessment of physical and biological properties and estimation of molecular diversity. The rules of Lipinski and Veber were applied to the molecular weight, the calculated water/n-octanol partition coefficients (Clog P), the calculated aqueous solubility (log S), the numbers of hydrogen-bond donors and acceptors, and the calculated Caco-2 membrane permeability to identify the drug-like compounds, whereas the toxicity/reactivity filters were used to remove the structures with biologically undesired functional groups. This filtering resulted in 2.0 million (39%) structures perfectly suitable for high-throughput screening of biological activity. Modified filters applied to identify lead-like structures revealed that 16% of the unique compounds could be potential leads. Assessment of the biological activities, the analysis of diversity, and the sizes of exclusive sets of compounds are presented.

Engineering crystals of dendritic molecules.

A detailed single-crystal X-ray study of conformationally flexible sulfonimide-based dendritic molecules with systematically varied molecular architectures was undertaken. Thirteen crystal structures reported in this work include 9 structures of the second-generation dendritic sulfonimides decorated with different aryl groups, 2 compounds bearing branches of both second and first generation, and 2 representatives of the first generation. Analysis of the packing patterns of 9 compounds bearing second-generation branches shows that despite their lack of strong directive functional groups there is a repeatedly reproduced intermolecular interaction mode consisting in an anchor-type packing of complementary second-generation branches of neighbouring molecules. The observed interaction tolerates a wide range of substituents in meta- and para-positions of the peripheral arylsulfonyl rings. Quantum chemical calculations of the molecule-molecule interaction energies agree at the qualitative level with the packing preferences found in the crystalline state. The calculations can therefore be used as a tool to rationalize and predict molecular structures with commensurate and non-commensurate branches for programming of different packing modes in crystal.

Antioxidant and antiradical activities of resorcinarene tetranitroxides.

Resorcinarene oxazines bearing four TEMPO fragments at the wide rim of the macrocycle were prepared through the aminomethylation of resorcinarene octols with 4-amino-TEMPO and formaldehyde. Tetra-TEMPO resorcinarenes are efficient scavengers of 1,1-diphenyl-2-picrylhydrazyl radicals. The model studies revealed that macrocyclic structure and intramolecular hydrogen bonding make considerable contribution to antiradical activity of these compounds. Tetra-TEMPO resorcinarenes show also superoxide dismutase-like activity and efficiently inhibit ABAP-induced peroxidation of linoleic acid.

Interaction energies and dynamics of acid-base pairs isolated in cavitands.

The use of capsules and cavitands in physical organic chemistry is briefly reviewed, and their application to the study of salt bridges is introduced. Carboxylate/ammonium ion pairs are generated within an environment that more or less surrounds the functional groups within a synthetic fixed introverted solvent sphere. This is provided by cavitands that fold around amines and present them with a carboxylic acid function. Both organic and water-soluble versions were prepared, and their equilibrium affinities with quinuclidine bases were determined by NMR methods. The association constants range from approximately 10(3) M(-1) in water to more than 10(5) M(-1) in organic solvents. Studies of nitrogen inversion and tumbling of [2.2.2]-diazabicyclooctane within the introverted acids also illustrate the strength of the acid-base interactions. The barriers to in-out exchange of several amine guests were determined to be in the range from 15 to 24 kcal mol(-1). Some parallels with enzymes are drawn: the receptor folds around the guest species; presents them with inwardly directed functionality; and provides a generally hydrophobic environment and a periphery of secondary amide bonds.

Synthesis of quinolines from 3-formylchromone.

A facile and versatile procedure for the synthesis of 3-(2-hydroxybenzoyl)quinolines and 7H-chromeno[3,2-c]quinolin-7-ones was elaborated on the basis of TMSCl-mediated recyclization of 3-formylchromone with various anilines. Limitations and scope of this methodology were established, and a possible mechanism for the heterocyclizations was proposed.

Nanoencapsulation of calix[4]arene inclusion complexes.

A hexameric resorcinarene nanocapsule in wet CDCl3 forms inclusion complexes of calix[4]arene with tetramethylammonium and trimethylsulfoxonium cations to give highly stable Russian-doll-type multicomponent assemblies. The 2D NOESY experiments revealed the size of the assembly, the close proximity of the encapsulated calix[4]arene molecule to the resorcinarene molecules of the capsule, and the inclusion of the tetramethylammonium cation in the calix[4]arene cavity.

A one-step fusion of 1,3-thiazine and pyrimidine cycles.

The chlorotrimethylsilane-promoted Biginelli type reactions of aldehydes, thiourea, and cyanoketones led to a diverse set of tetrahydropyrimidine-2(1H)-thiones. Under similar conditions, thioureas, benzaldehyde, and cyanoacetamide reacted to give first representatives of hexahydro-5H-pyrimido[5,4-e][1,3]thiazin-5-ones in high preparative yield.

Combinatorial Knoevenagel reactions.

Chlorotrimethylsilane (TMSCl) has been utilized as an efficient promoter and water scavenger in the Knoevenagel condensations of aromatic aldehydes with various methylene active compounds. High yields and a simple workup of target compounds enables the facile generation of combinatorial libraries comprising 11,000 compounds of high structural and functional diversity.

One-pot synthesis of 2,3-dihydro-1H-benzimidazoles.

A convenient one-pot method for the synthesis of 2,3-dihydro-1H-benzimidazoles has been elaborated. A set of 2,3-dihydro-1H-benzimidazoles was prepared from various ortho-dialkylaminoanilines and aldehydes using Me3SiCl as a condensation agent and pyridine as a basic medium.

Calix[4]arene alpha-aminophosphonic acids: asymmetric synthesis and enantioselective inhibition of an alkaline phosphatase.

[structure: see text] Chiral calix[4]arene alpha-aminophosphonic acids were obtained through diastereoselective Pudovik-type addition of sodium ethyl phosphites to the chiral calixarene imines, removal of chiral auxiliary groups, and mild dealkylation of phosphonate fragments. The diacids obtained show inhibitory activity toward porcine kidney alkaline phosphatase that depends considerably on the absolute configuration of the alpha-carbon atoms.

Resorcinarene assemblies as synthetic receptors.

The host-guest complexes of resorcinarenes are re-examined in solution through modern spectroscopic methods; the assemblies are characterized by 1H NMR and the guest exchange rates are measured by EXSY NMR spectroscopy.

Enhanced thermodynamic and kinetic stability of calix[4]arene dimers locked in the cone conformation.

Wide rim tetraurea derivatives (2a,b) have been prepared from a calix[4]arene rigidified in the cone conformation by two diethyleneglycol ether bridges between adjacent oxygens. In comparison to the analogous tetraurea derivatives (3a,b) of a tetrapentoxy calix[4]arene, 2a,b show an increased thermodynamic stability in mixtures of CDCl(3) and DMSO-d(6). Their kinetic stability as expressed by the rate of guest exchange (benzene or cyclohexane against the solvent benzene-d(6)) is also strongly increased by factors of 30-38. Noticeable differences for the inclusion of selected guests are found.

Alkoxy-, acyloxy-, and bromomethylation of resorcinarenes.

Reaction of resorcinarene octols with tris-hydroxymethylmethylamine (TRIS), formaldehyde, and alcohols results in tetraalkoxymethylation of the resorcinol rings. Harsh acylation of aminomethylated resorcinarenes with acid anhydrides leads to the complete acylation of eight hydroxyls and substitution of the amino versus acyloxy groups. Acyloxymethylated resorcinarene 6b can be transformed into a tetrabromomethylated derivative 7 through the reaction with HBr in acetic acid.

Selective mono-O-acylation of C2V-symmetrical calix[4]arenediols with acylisocyanates.

Calix[4]arenedialkyl ethers 3 react with an excess of acylisocyanates to give selectively monoacylated products 4. Intramolecular hydrogen bonds and steric effects of the acylcarbamate fragments are most likely responsible for the high selectivity of this monoprotection. [reaction: see text]

Sterically and guest-controlled self-assembly of calix[4]arene derivatives.

In solvents such as chloroform or benzene, tetraurea calix[4]arenes 1 form dimeric capsules in which one solvent molecule is usually included as guest. To explore the structural requirements for the formation of such hydrogen-bonded dimers we replaced one p-tolylurea residue by a simple acetamide function. The resulting calix[4]arene 2 a, substituted at its wide rim with one acetamide and three p-tolylurea functions, assumes a C(1)-symmetrical conformation in apolar solvents as shown by (1)H NMR, which is not compatible with the usual capsule. In the crystalline state, four molecules of 2 a, adopting a pinched cone conformation, assemble into a quasi S(4)-symmetrical tetramer stabilized by a cyclic array of 24 NH.O==C hydrogen bonds and four NH.pi interactions. Four acetamide groups are hydrogen-bonded to each other and pack tightly in the center of the assembly. All polar residues are buried inside the tetramer, the surface of which is lipophilic. Extensive NMR studies revealed similar structures in apolar solvents such as [D]chloroform or [D(6)]benzene for calixacetamides 2 a-c. The formation of these tetramers in solution is critically dependent on the size of the amide fragment, so that propionamide 2 d, butyramide 2 e, and p-tolylamide 2 f form only ill-defined aggregates. This is caused by steric crowding inside the tetrameric assembly. The tetramers persist during molecular dynamics simulations, and the optimized average structure of the MD run is similar to that found in the crystalline state. Theoretical studies revealed that cooperation of hydrogen bonds with multiple NH.pi, C--H.pi, and pi.pi attractions make the tetramer more stable than the capsular dimer with the solvent as guest. In the presence of tetraethylammonium salts, however, compounds 2 a-e form dimeric capsular assemblies, each incorporating a single ammonium cation. Only one of two possible regioisomeric dimers is formed, in which both acetamide groups are surrounded by two urea residues. These examples give striking evidence of how self-assembly in solution can be strongly dependent on subtle structural factors and of how the formation of dimeric capsules can be induced by the presence of an appropriate guest.

Kinetics and thermodynamics of hexameric capsule formation.

Resorcinarene 1b forms a hexameric assembly in water-saturated CDCl(3) that encapsulates one tetraalkylammonium salt (2(+)Br(-)). The remaining space is occupied by coencapsulated solvent molecules. A maximum of three and minimum of one CHCl(3) molecule were found inside of capsules with tetrapropyl- and tetraheptylammonium bromide, respectively. The encapsulation of the salt is endothermic and entropically favored by the liberation of the solvent molecules. The stabilities of the encapsulation complexes and the rates of guest exchange decrease for larger cations. The higher activation barriers for in/out exchange of the larger guests suggest tight conformational restraints in the transition state. It is likely that complete dissociation of one resorcinarene molecule is necessary for the exchange of the alkylammonium salts.

Stereochemistry in self-assembled encapsulation complexes: constellational isomerism.

A previously uncharacterized form of stereochemistry, constellational isomerism, is described. The isomerism arises from different arrangements of small-molecule guests in the space of a self-assembled, cylindrical host. The cylindrical host detains three molecules each of CHCl(3), 1,2-dichloroethane, or isopropyl chloride. The exchange of guests in and out of the host is slow on the NMR time scale. The dimensions of the capsular host and the sizes of the guests hinder the mobility of molecules inside, and separate NMR signals are seen for guests at the ends of the capsule and those near its center. When two different guests are encapsulated, the spectra show up to four additional species: two sets of constellational isomers. In every pairwise combination of the three guests, all isomers could be identified. The equilibrium distributions of isomers depended on the concentrations of the guests in the bulk solution. The relative stability of the constellational isomers was a function of the polarity of the guest molecule and its ability to interact with the components of the capsule. The different arrangements represent information, and some possibilities for their use in data storage are proposed.