Self-assembled dendrimers with uniform structure

Calix[4]arenes substituted at their wide rim by four aryl urea residues (1) form hydrogen-bonded dimers in apolar solvents. Replacement of one urea residue by an acetamido moiety leads to calix[4]arene derivatives (5) which form hydrogen-bonded tetramers under the same conditions. Both self-assembly processes occur independently. Therefore, molecules have been prepared in which a tetra-urea calix[4]arene and a tri-urea mono acetamide derivative are covalently connected between their narrow rims by a long, mainly aliphatic chain [-O-(CH(2))(n)-C(O)-NH-(CH(2))(m)-O-] (7). In the presence of an equimolar amount of tetra-tosyl urea calix[4]arene () they form dendritic assemblies since the well known heterodimerization of tetra-tosyl and tetra-aryl urea calix[4]arenes prevents the formation of a cross-linked structure. Covalent connection of adjacent urea residues leads to tetra-loop derivatives (3) that cannot form homodimers, but instead form heterodimers with tetra-aryl or tetra-tosylureas. Therefore, similar dendrimers should be available using the selective dimerization observed for 3. The formation of a single, structurally uniform dendrimer from eight building blocks is confirmed by (1)H NMR spectra, showing only peaks that are also found for respective model assemblies. Translational diffusion coefficients of the assemblies have been determined using (1)H DOSY NMR.     

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.     

Topologically novel multiple rotaxanes and catenanes based on tetraurea calix[4]arenes

Calix[4]arenes bearing at their wide rim four urea residues easily form hydrogen bonded dimeric capsules. This has been used to preorganise alkenyl functions attached to these urea groups for their controlled connection via metathesis reaction. Multimacrocyclic tetraurea derivatives are thus obtained in excellent yields via heterodimers which are formed exclusively with tetratosylurea derivatives. Heterodimerisation of such bis- and tetraloop tetraureas leads analogously to multicatenanes, or to rotaxanes by stoppering. Huge macrocycles are detached from tetraloop derivatives by cleavage of the urea function.     

Wide rim urethanes derived from calix[4]arenes: synthesis and self-assembly

[reaction: see text] Calix[4]arenes 4, substituted at the wide rim by four N-tolyl-urethane groups, were synthesized, as well as derivatives 10a,b bearing two or three tolyl-urea groups beside of one or two urethane group(s). In contrast to tetra-tolyl urea 11, the urethane derivatives do not form hydrogen-bonded, dimeric capsules in CDCl3 or benzene-d6, but the dimerization can be induced for the triurea 10b by tetraethylammonium cations as guests. The quantitative formation of heterodimers is observed for all urethanes 4 and 10a,bin benzene-d6 in mixtures with a "tetra-loop" tetraurea 14, while "bisloop" tetraureas 13 require di- or triurea derivatives 10a,b for a clean heterodimerization.     

Hydrogen bonded homo- and heterodimers of tetra urea derivatives of calix[4]arenes

Calix[4]arene ethers fixed in the cone conformation and substituted at the upper rim by various urea residues have been synthesized by reaction of the amino calix[4]arenes with isocyanates. Their dimerisation in apolar solvents has been established by the formation of mixed dimers consisting of two different urea derivatives.     

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.     

Do pentaurea calix[5]arenes form hydrogen bonded dimeric capsules?

Calix[5]arenes substituted at their wider rim by five urea residues do not form hydrogen bonded dimeric capsules in aprotic, apolar solvents, in contrast to their calix[4]arene analogs, although molecular dynamic simulations predict very similar geometrical parameters for both cases. The reason for this different behavior is most probably the higher energetic cost which must be paid to arrange the calix[5]arene skeleton in the C₅-symmetrical conformation required for the dimerization.     

Versatile access to benzhydryl-phenylureas through an unexpected rearrangement during microwave-enhanced synthesis of hydantoins

[reaction: see text] A new access to benzhydryl-phenylureas is described. These new interesting urea derivatives were obtained by reaction of substituted benzils with substituted phenylureas under microwave irradiation. Phenylthiourea, when reacted with benzil, gave 3-phenyl-thiohydantoin. Moreover, benzylurea, as phenethylurea, gave the corresponding 3-substituted hydantoin derivatives, demonstrating that only phenylurea derivatives can result in benzhydryl-phenylureas under the applied conditions. This new reaction proved to be an easy access to substituted 1-benzhydryl-3-phenyl-ureas.     

Functional [6]pericyclynes: synthesis through [14+4] and [8+10] cyclization strategies

Critical analysis of possible strategies for the synthesis of novel carbo-benzene derivatives suggests several [(18-n)+n] routes for the preparation of hexaoxy[6]pericyclyne precursors. Beyond the previously attempted [9+9] symmetrical scheme (n=9), the a priori most selective strategies are those for which n=1, 4, 7, 10, 13, and 16. They involve a cyclizing double-propargylation of a C(18-n) omega-bis-terminal-skipped oligoyne containing (19-n)/3 triple bonds with a C(n) omega-dicarbonyl-skipped oligoyne containing (n-1)/3 triple bonds. To complement the previously used [11+7] strategy, the [14+4] and [8+10] strategies were thus explored. They proved to be efficient, affording seven novel hexaoxy[6]pericyclynes corresponding to six different substitution patterns. These compounds were obtained in 7-15 steps as mixtures of stereoisomers. Thus, by using dibenzoylacetylene as the C(4) electrophile, a [14+4] strategy allowed the synthesis of two hexaphenyl representatives with two or four free carbinol vertices. This approach also afforded tetraphenyl representatives in which the two remaining carbinoxy vertices were substituted with either two alkynyl or one 4-anisyl and one 4-pyridyl groups. By using the hexacarbonyldicobalt complex of butynedial as the C(4) electrophile, a [14+4] strategy also allowed the isolation of a tetraphenylhexaoxy[6]pericyclyne with two adjacent unsubstituted carbinol vertices. A regioisomer with two opposite unsubstituted carbinol vertices was obtained through an [8+10] strategy and its oxidation afforded the corresponding pericyclynedione. Several attempts at synthesizing diphenylhexaoxy[6]pericyclynes with four unsubstituted carbinoxy vertices are described. Only an [8+10] strategy allowed the generation of a fragile diphenylhexaoxy[6]pericyclyne with four adjacent unsubstituted carbinoxy vertices, which could be partly characterized. These results show that the synthesis of the nonsubstituted hexahydroxy[6]pericyclyne, the ring carbo-mer of [6]cyclitol, is a difficult challenge.     

The Study on Synthesis of Some New 1,2,3‐Triazolylurea and Carbonyl Amide Derivatives

The study on syntheses of some N‐substituted‐N′‐[5‐methyl‐1‐(4‐chlorophenyl)‐1,2,3‐triazol‐4‐yl]‐urea 6a‐e and N‐substituted‐[5‐methyl‐1‐(4‐chlorophenyl)‐1,2,3‐triazol‐4‐yl]carbonyl amide 6f‐l derivatives were reported in this paper. The yielded products 6a‐l were confirmed by elemental analyses, NMR, MS and IR spectra.     

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.     

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.     

Supramolecular structures formed by calix[8]arene derivatives

Octamethoxy calix[8]arenes substituted in the para position by amide, urea, and imide functions were synthesized from the octamethyl ether of tert-butylcalix[8]arene by ipso nitration, reduction, and acylation. Scanning force microscopy of spin coated samples on graphite suggests that these derivatives self-organize into tubular nanorods via hydrogen bonds between p-amide functions. A single-crystal X-ray structure reveals a centrosymmetric conformation for the octanitro derivative. [structure: see text]     

Guest exchange in dimeric capsules formed by tetra-urea calix[4]arenes

Ten tetra-urea calix[4]arene derivatives with different ether residues (methyl, pentyl, benzyl, all combinations of methyl and pentyl, 1,3-dibenzyl-2,4-dipentyl), including also the tetrahydroxy compound and the 1,3-dipentyl ether, were synthesised. Their urea groups were substituted with a lipophilic residue to ensure sufficient solubility in cyclohexane. Thus, kinetics for the exchange of the included guest (benzene) against the solvent (cyclohexane) could be followed by 1H NMR spectroscopy. The apparent first order rate constants decrease with increasing size of the ether residues from methyl to benzyl by more than three orders of magnitude. This can be understood by a decreasing flexibility/mobility of the calixarene skeleton. In line with this explanation is the rather slow exchange for the tetrahydroxy compound, where the cone conformation is stabilised by a cyclic array of intramolecular OH...OH hydrogen bonds.     

Molecules with new topologies derived from hydrogen-bonded dimers of tetraurea calix[4]arenes

Tetraurea calix[4]arenes 2 have been synthesized in which two adjacent aryl urea residues are connected to a loop by an aliphatic chain -O-(CH(2))(n)-O-. The remaining urea residues have a bulky 3,5-di-tert-butylphenyl residue and an omega-alkenyloxyphenyl residue. Since this bulky residue cannot pass through the loop, only one homodimer (22) is formed in apolar solvents, for steric reasons, in which the two alkenyl residues penetrate the two macrocyclic loops. Covalent connection of these alkenyl groups by olefin metathesis followed by hydrogenation creates compounds 3, which consist of molecules with hitherto unknown topology. Their molecular structure was confirmed by (1)H NMR spectroscopy and ESIMS, and for one example by single-crystal X-ray analysis.     

Tetraurea calix[4]arenes with sulfur functions: synthesis, dimerization to capsules, and self-assembly on gold

Various calix[4]arene derivatives, fixed in the cone conformation by decylether groups and functionalized at their wide rim by urea residues, were synthesized. In two compounds (,) sulfur functions were attached to the urea groups via different spacers in order to allow binding to metal surfaces. While they exist as single molecules in polar solvents, tetraurea calix[4]arenes of this type () combine to form dimeric capsules in aprotic, apolar solvents. A solvent molecule is usually included in such a capsule, if no guest with a higher affinity is present. In the presence of an equimolar amount of the tetratosylurea, the exclusive formation of heterodimers, consisting of one molecule of and, is observed. The homo- and heterodimerization of the newly prepared derivatives, were studied by 1H NMR to establish the conditions under which they exhibit the desired dimerization behaviour. Self-assembled monolayers (SAMs) were formed using the single calix[4]arenes, and the heterodimeric capsules. Chloroform, dichloromethane and ferrocenium cations were used as guests in these immobilized heterodimeric capsules. The particular supramolecular architecture of the heterodimers should ensure that, after the immobilization on the metal surface, decomposition of the capsules and release or exchange of the guest is impossible or at least hindered. The self-assembly process and the stability of SAMs formed by capsules filled with ferrocenium cations in electrolyte solutions were tested with surface plasmon spectroscopy. The inclusion of guests, such as dichloromethane or ferrocenium, in the immobilized capsules were confirmed by classical surface plasmon spectroscopy, by gold nanoparticle absorption spectroscopy and by time-of flight secondary ion mass spectrometry (ToF-SIMS). The film stability and quality was tested by cyclic voltammetry.     

On triazoles XXX. Synthesis of [1,2,4]triazolo-[1,5-d][1,2,4,6]tetrazepine-5-thiones

Different 2-Q-6,7,8,9-(bi-, tri- or tetra)substituted[1,2,4]triazolo[1,5-d][1,2,4,6]tetrazepine-5-triione derivatives representing a novel ring system were synthesised. In the case of 8-aryl-substituted derivatives ring-chain tautomerism was observed in DMSO-d₆ or deuteriochloroform solutions. In some cases both ring and chain tautomers could be isolated in crystalline form. The structure of products obtained was proved by nmr using also model compounds prepared for this purpose.     

Catalytic Desymmetric Cycloaddition of Diaziridines with Metalloenolcarbenes: The Role of Donor–Acceptor Cyclopropenes

A chiral copper(I) complex catalyzes reactions of symmetric diaziridines with enol diazo compounds, which react through N?N bond ring opening in a formal [3+3] cycloaddition to form four chiral centers with high stereocontrol. A broad spectrum of bridged dinitrogen heterocycles were obtained in high yields and excellent diastereo‐ and enantioselectivities from γ‐substituted enol diazoacetates, while their geometrical isomers gave different enantioselectivities. Donor–acceptor cyclopropenes formed from the geometrical isomers of the γ‐substituted enol diazoacetates underwent catalytic ring opening to give only the Z isomer of the metalloenolcarbene intermediate, provided excellent yields and selectivities for the 1,5‐diazabicyclo[n.3.1]non‐2‐ene derivatives.     

Solid-phase synthesis of imidazo[4,5-b]pyridin-2-ones and related urea derivatives by cyclative cleavage of a carbamate linkage

A solid-phase synthesis of substituted cyclic urea derivatives as potential heterocyclic library scaffolds is described. 2-Amino-3-nitropyridine is attached to Wang resin via a carbamate linkage. Reduction of the nitro group was achieved with SnCl(2).2H(2)O. Reductive alkylation with a range of substituted benzaldehydes followed by cyclative cleavage afforded a small library of 3-substituted imidazo[4,5-b]pyridine-2-ones in 33-45% yield and 59-88% purity. Subsequently, this methodology was applied to the synthesis of 3-substituted imidazo[4,5-f]quinolin-2-ones.     

Curtius rearrangement of aromatic carboxylic acids to access protected anilines and aromatic ureas

The reaction of a chloroformate or di-tert-butyl dicarbonate and sodium azide with an aromatic carboxylic acid produces the corresponding acyl azide, presumably through the formation of an azidoformate. The acyl azide undergoes a Curtius rearrangement to form an isocyanate derivative which is trapped either by an alkoxide or by an amine to form the aromatic carbamate or urea. The reaction conditions are compatible with a variety of functional groups and allow the synthesis of a number of aniline derivatives containing alkyl, halide, nitro, ketone, ether, and thioether substituents. [reaction: see text]