Rotaxanes and Catenanes Derived from Tetra-Urea Calix[4]arenes

Summary: Calix[4]arenes, substituted by four urea groups at their wide rim, form dimeric capsules in apolar solvents, which are held together by a seam of intermolecular hydrogen bonds. The heterodimerisation of tetra-aryl and tetratosyl ureas was used to synthesize various derivatives, in which adjacent urea residues are connected to form two, three or four loops. The aliphatic connections were tied by olefin metathesis between adjacent alkenyl residues followed by hydrogenation. Heterodimers of tetra-alkenyl substituted tetra-ureas and bis- or tetraloop derivatives were converted analogously to multiple catenanes. Tetra[2]rotaxanes were obtained in a similar manner. In addition to the spectroscopic evidence (NMR, MS) several compounds were confirmed by crystal structures.     

Self-sorting dimerization of tetraurea calix[4]arenes

Calix[4]arenes substituted by four urea functions are self-complementary molecules that spontaneously combine in apolar solvents in the presence of an ammonium salt to form dimeric capsules held together by a belt of hydrogen bonds. In the presence of tetraethylammonium salts, the Et4N+ cation is included as a guest. The sorting between dimeric capsules formed in a mixture of calix[4]arenes directly depends on the steric crowding of the substituents grafted on the urea groups whether aromatic derivatives or aliphatic chains linking urea functions in mono-, di-, or tetraloop structures. Simple rules allow one to anticipate which capsules will be exclusively formed when calix[4]arenes are mixed in different proportions. The stabilization of the dimeric structures by hydrogen bonds is thwarted by the overlaps of aliphatic loops and/or by bulky groups that cannot pass through these loops. Despite the structural similarity of the calixarenes, the exclusive formation of dimers of well-defined compositions and clear titration breaks are observed by electrospray mass spectrometry. This technique yields reliable information on stoichiometries and composition despite measurements in the gas phase rather than in solution and it does not suffer from excessive peak overlaps in contrast with NMR.     

Kinetic barriers in the isomerization of substituted ureas: implications for computer-aided drug design

Urea derivatives are ubiquitously found in many chemical disciplines. N,N′-substituted ureas may show different conformational preferences depending on their substitution pattern. The high energetic barrier for isomerization of the cis and trans state poses additional challenges on computational simulation techniques aiming at a reproduction of the biological properties of urea derivatives. Herein, we investigate energetics of urea conformations and their interconversion using a broad spectrum of methodologies ranging from data mining, via quantum chemistry to molecular dynamics simulation and free energy calculations. We find that the inversion of urea conformations is inherently slow and beyond the time scale of typical simulation protocols. Therefore, extra care needs to be taken by computational chemists to work with appropriate model systems. We find that both knowledge-driven approaches as well as physics-based methods may guide molecular modelers towards accurate starting structures for expensive calculations to ensure that conformations of urea derivatives are modeled as adequately as possible.     

Stepwise synthesis and selective dimerisation of bis- and trisloop tetra-urea calix[4]arenes

Tetra-urea calix[4]arenes substituted with four mono- or bisalkenyl residues have been converted into bis- or tetraloop compounds by intramolecular olefin metathesis, with use of a tetratosylurea calix[4]arene as template. The same strategy has now been used to synthesise trisloop compounds and bisloop compounds with adjacent loops, completing the series of the loop-containing tetra-urea derivatives. A tetra-urea calix[4]arene of the AABB type, where A stands for a bisalkenyl- and B for a monoalkenyl-substituted urea unit, was used as precursor for the three loops. It was easily synthesised from a tetraamino calix[4]arene in which two adjacent amino groups were Boc-protected. The ABCB-type precursor for the two adjacent loops was prepared through protection of two opposite amino functions with trityl groups. The capabilities of the novel macrocyclic tetra-ureas for the selective formation of hydrogen-bonded dimers were studied.     

Multiple catenanes based on tetraloop derivatives of calix[4]arenes

Four novel tetraarylurea calix[4]arenes (4a-d) have been synthesized, substituted by ω-alkenyloxy residues in 3,5-positions of the arylurea residues. The eight alkenyl groups were pairwise connected by olefin metathesis and subsequent hydrogenation. The ring-closure reaction was carried out with heterodimers exclusively formed by 4 with a tetratosylurea calix[4]arene 1, which serves as a template in this reaction step. The potential trans-cavity bridging is entirely suppressed in this way. Bis- and tetraloop calix[4]arenes cannot form dimers due to overlapping loops. However, they readily form heterodimers with open-chain tetraureas, as long as their urea residues can pass through the loops. Thus, five heterodimeric capsules 8a-e with bis[3]catenane structure were synthesized using again the olefin metathesis followed by hydrogenation. Two different strategies were compared for this reaction sequence, starting with heterodimers formed either by tetraloop derivatives 5 with tetraalkenyl tetraureas 6 (pathway A) or by bisloop derivatives 7 with octaalkenyl tetraureas 4 (pathway B). A distinct advantage of one of these pathways was not observed; the bis[3]catenanes were obtained with yields of 20-60%. Heterodimers formed by tetraloop derivatives 5b-d and octaalkenyl ureas 4b-d were converted analogous to three novel cyclic [8]catenanes 9a-c in 30-42% yield. The structure of the novel catenanes was unambiguously proved by ¹H NMR and ESI MS, and for 8a and 9a additionally by single crystal X-ray analysis.     

Lewis base catalysis by thiourea: N-bromosuccinimide-mediated oxidation of alcohols

In recent times, (thio)urea derivatives have become synonymous with hydrogen bonding owing to their extensive applicability as small molecule organocatalysts. In this paper, another activation mode by thiourea derivatives, namely via Lewis base catalysis, is disclosed for the NBS-mediated oxidation of alcohols. The mild reaction conditions employed here is suitable for chemoselective oxidation of secondary alcohol in the presence of primary alcohol.     

Oxidation of N-substituted dopamine derivatives: irreversible formation of a spirocyclic product

Oxidation of amide, urea and guanidinium derivatives of dopamine gives relatively stable ortho-quinones whereas oxidation of corresponding thioamide and amidinium derivatives rapidly and quantitatively gives novel bicyclic and spirocyclic products formed via the corresponding ortho-quinone.     

Synthesis,Crystal Structure,Fungicidal Activities and Molecular Docking of Acyl Urea Derivatives Containing 2-Chloronicotine Motif

Eighteen new acyl urea derivatives containing 2-chloronicotine moiety were synthesized using2-chloronicotinic acid as starting material via 4 steps conveniently.These 2-chloronicotine acyl urea structures were confirmed by ¹H NMR,¹³C NMR and HRMS.Compound 4r was further confirmed by X-ray diffraction.It crystallizes in the orthorhombic system,space group Pbca with a=7.2960（3）,b=14.8546（6）,c=25.2840（11）?,V=2740.3（2）?³,Z=8,the final R=0.0442 and w R=0.1033 for 4028...     

Facile synthesis of a diverse library of mono-3-substituted β-cyclodextrin analogues

Substituted cyclodextrins (CDs) have many applications, but synthetic challenges have limited the derivatives that can routinely be accessed. In particular, although there is considerable interest in selective derivatization at the 2- and 3-hydroxyls on the secondary face, since bulky guest molecules are most likely to project through this larger aperture, syntheses of such derivatives have required arduous procedures that afford poor yields, limiting their accessibility and utility. We address this challenge via synthetic strategies that allow facile creation of diverse libraries of water-soluble mono-3-substituted-β-cyclodextrins, via the commercially available mono-3-amino-β-cyclodextrin. The power of these strategies is confirmed through synthesis of twenty water-soluble cyclodextrin analogues with amide, thioureas or urea linkers, using one-pot reactions producing ≥55% yields and purifications that do not require chromatography. This work opens new possibilities for the design of selective host molecules for use in supramolecular chemistry, chemical separations, pharmaceutical formulations, and calibration of molecular simulations.     

Perfluoro(1,2-epoxycyclohexane) in the synthesis of fluorinated heterocycles

Perfluoro(1,2-epoxycyclohexane) readily reacts with bifunctional nucleophiles (urea, thiourea, and benzene-1,2-diamine) via opening of the oxirane ring and subsequent heterocyclization to give fluorinated benzimidazole, 1,3-benzothiazole, and phenazine derivatives, respectively.     

A new and convenient one-pot solid supported synthesis of 2,4,6-triarylpyridines

A new, convenient, efficient and cost-effective one-pot solid supported synthesis of 2,4,6-triarylpyridines from benzylideneacetophenones and urea, thiourea or their derivatives, using Bi(III) nitrate-Al₂O₃ is described. The reaction seems to proceed via β-oxygenation of Bi(III)-enolized benzylideneacetophenone followed by Michael addition, heteroannulation with simultaneous retro aldol disproportionation and subsequent catalytic oxidation and dehydration.     

PET suppression of acridinedione dyes by urea derivatives in water and methanol

Spectroscopic investigations involving the interaction of acridinedione dyes with urea and its derivatives in water and methanol were carried out by absorption, steady-state fluorescence, and time-resolved fluorescence measurements. The hydrogen-bonding properties of urea and derivatives in aqueous solutions are found to be distinctly different from those observed in methanol. Urea, which can serve both as a hydrogen bond donor as well as an acceptor and has a unique hydrogen-bonding feature, helps in studying urea interaction with fluorophores in aqueous solutions, micelles, and alcohol. In our studies, we have used acridinedione dyes as the probe. We report that the hydrophobic interaction of urea with dye predominates by weakening of the hydrogen-bonding interaction of the solvent and urea derivatives with increase in the hydrophobicity of urea derivatives. In methanol, the hydrogen bonding between solvent and urea derivatives predominating over the hydrophobicity of the urea derivatives is observed. The presence of alkyl group substitution in the N-H moiety with a function of increasing concentration resulting in the creation of a more favorable hydrophobic environment to the dye molecule to reside in the hydrophobic shell phase rather than in the bulk aqueous phase is illustrated. The hydrophobic interaction of dye with urea in aqueous solution predominates because of the weakening of the hydrogen bonding of the solvent and urea derivatives, and the photoinduced electron transfer (PET) process is used as a marker to identify the hydrophobic interaction illustrated in our studies.     

Enzymatic Hydrolysis-Responsive Supramolecular Hydrogels Composed of Maltose-Coupled Amphiphilic Ureas

Maltose is a ubiquitous disaccharide produced by the hydrolysis of starch. Amphiphilic ureas bearing hydrophilic maltose moiety were synthesized via the following three steps: I) construction of urea derivatives by the condensation of 4-nitrophenyl isocyanate and alkylamines, II) reduction of the nitro group by hydrogenation, and III) an aminoglycosylation reaction of the amino group and the unprotected maltose. These amphiphilic ureas functioned as low molecular weight hydrogelators, and the mixtures of the amphipathic ureas and water formed supramolecular hydrogels. The gelation ability largely depended on the chain length of the alkyl group of the amphiphilic urea; amphipathic urea having a decyl group had the highest gelation ability (minimum gelation concentration=0.4 mM). The physical properties of the supramolecular hydrogels were evaluated by measuring their thermal stability and dynamic viscoelasticity. These supramolecular hydrogels underwent gel-to-sol phase transition upon the addition of α-glucosidase as a result of the α-glucosidase-catalyzed hydrolysis of the maltose moiety of the amphipathic urea.     

Sonication-induced self-assembly of flexible tris(ureidobenzyl)amine: from dimeric aggregates to supramolecular gels

Tris(ureidobenzyl)amine derivatives 1a,b form dimeric aggregates in apolar solution and in the solid state. Specifically, the meta-substituted tris(urea) 1a is able to transform into supramolecular gels in certain solvents via sonication.     

Amide,urea and thiourea‐containing triphenylene derivatives: influence of H‐bonding on mesomorphic properties

The synthesis and thermotropic properties are reported for a series of hexaalkoxytriphenylenes that contain an amide, urea or thiourea group in one of their alkoxy tails. The intermolecular hydrogen bonding abilities of these molecules have a disturbing influence on the formation and stability of the columnar liquid crystalline phases. The stronger the hydrogen bonding the more the liquid crystallinity is suppressed, probably due to disturbance of the π–π stacking of the triphenylene discs. As a direct result, urea‐ and amide‐containing triphenylene derivatives are not liquid crystalline, but several thiourea derivatives show hexagonal columnar mesophases.     

Carbonylation of functionalized diamine diols to cyclic ureas: application to derivatives of DMP 450

Synthesis of the cyclic urea core structure of the HIV protease inhibitor DMP 450 has been achieved via W(CO)₆/I₂-catalyzed carbonylation of diamine intermediates. Carbonylations of related functionalized diamines to derivatives of the DMP 450 core structure were also examined. Selected diamine diol substrates could be converted to the cyclic urea core structure by catalytic carbonylation without protection of the diol functionality.     

Pyridine-incorporated cyclo[6]aramide for recognition of urea and its derivatives with two different binding modes

Abstract

A novel pyridine-incorporated cyclo[6]aramide is designed and synthesised for recognition of urea and its derivatives. Analysis of its single crystal structure reveals the presence of introverted amide NH protons and amide carbonyl groups that are supposed to contribute to the subsequent accommodation of neutral urea-related guest molecules via multiple hydrogen bonding interactions. Thiourea is found to be superior to urea in binding to the receptor. Particularly interesting is the observation of two binding modes in complexing urea/thiourea (contact mode) and ethylurea/diethylurea (threading mode) as supported by both NMR experiments and computational simulations. The finding of the threading mode may open up new opportunities for the development of pesudorotaxanes and related mechanically interlocked structures.     

Copper-catalyzed one-pot process to construct triazole-linked urea derivatives

A new one-pot synthetic methodology has been developed to construct the triazole-linked urea derivatives. In the same step, triazole forms from azide and alkyne via click reaction and urea forms from addition reaction of amines and isocyanates. The notable features of this work include wide substrate scope, atom economy, environmental friendliness, and easily accessible starting materials. The preliminary biological screening of synthesized compounds show promising cytotoxic activity in basal cell carcinoma (BCC) cell lines.     

STRUCTURE OF SOME ADAMANTYL-CONTAINING UREAS AND HYDROGEN BONDS IN THEIR CRYSTALS

Journal of Structural Chemistry - Molecular and crystal structures of five substituted urea derivatives with bulky adamantyl fragments in their substituents are considered. It is shown that the...     

Tertiary interactions determine the accuracy of RNA folding

RNAs must fold into unique three-dimensional structures to function in the cell, but how each polynucleotide finds its native structure is not understood. To investigate whether the stability of the tertiary structure determines the speed and accuracy of RNA folding, docking of a tetraloop with its receptor in a bacterial group I ribozyme was perturbed by site-directed mutagenesis. Disruption of the tetraloop or its receptor destabilizes tertiary interactions throughout the ribozyme by 2-3 kcal/mol, demonstrating that tertiary interactions form cooperatively in the transition from a native-like intermediate to the native state. Nondenaturing PAGE and RNase T1 digestion showed that base pairs form less homogeneously in the mutant RNAs during the transition from the unfolded state to the intermediate. Thus, tertiary interactions between helices bias the ensemble of secondary structures toward native-like conformations. Time-resolved hydroxyl radical footprinting showed that the wild-type ribozyme folds completely within 5-20 ms. By contrast, only 40-60% of a tetraloop mutant ribozyme folds in 30-40 ms, with the remainder folding in 30-200 s via nonnative intermediates. Therefore, destabilization of tetraloop-receptor docking introduces an alternate folding pathway in the otherwise smooth energy landscape of the wild-type ribozyme. Our results show that stable tertiary structure increases the flux through folding pathways that lead directly and rapidly to the native structure.