Pulsed gradient spin echo (PGSE) diffusion measurements as a tool for the elucidation of a new type of hydrogen-bonded bicapsular aggregate

Compounds formed by linking two tris(ureidobenzyl)amine modules with a hexamethylene tether are described. These compounds self-assemble to form bicapsular aggregates featuring two rings of six hydrogen-bonded ureas. (1)H and (1)H/(1)H ROESY NMR spectroscopy, together with pulsed gradient spin echo (PGSE) NMR diffusion measurements, have been used to characterize the dimers in solution. The results have been compared with energy-minimized structures. The new compounds are kinetically stable on the NMR timescale, and their thermodynamic stabilities are comparable to other capsular aggregates derived from tris(ureidobenzyl)amines.     

Development of C3‐Symmetric Tris‐Urea Low‐Molecular‐Weight Gelators

This article describes recent developments in C₃‐symmetric tris‐urea low‐molecular‐weight gelators and their applications. The C₃‐symmetric tris‐ureas are excellent frameworks to form supramolecular polymers through noncovalent interactions. In organic solvents, hydrophobic tris‐ureas form supramolecular gels. Amphiphilic tris‐ureas form supramolecular gels in aqueous media. Functional supramolecular gels were prepared by introducing appropriate functional groups into the outer sphere of tris‐ureas. Supramolecular hydrogels obtained from amphiphilic tris‐ureas were used in the electrophoresis of proteins. These electrophoreses results showed several unique characteristics compared to typical electrophoreses results obtained using polyacrylamide matrices.

     

From a monomer to a protein-sized, doughnut-shaped coordination oligomer-the influence of side chains of C3-symmetric ligands in supramolecular chemistry

Herein we describe the importance of side chains in C3-symmetric ligands in supramolecular chemistry. The reaction of the new ligand tris(5-bromo-2-methoxybenzylidene)triaminoguanidinium chloride [H3Me3Br3L]Cl (1) with ZnCl2 results in the formation of the monomeric complex (Et3NH)2[(ZnCl2)3Me3Br3L] (2), in which the ligand remains in a conformation less favourable for the coordination of metal centres. The use of the related tris(5-bromo-2-hydroxybenzylidene)triaminoguanidinium chloride, [H6Br3L]Cl, under similar conditions, results in the formation of two different dimeric compounds (NH4)[{[Zn(NH3)]3Br3L}2{mu-(OH)}3]1/4MeOH (3) and [Zn{Zn2(OH2)3(NH3)Br3L}2] (4), depending on the solvent mixture used. The comparable reaction of the ligand tris(5-bromo-2-hydroxy-3-methoxybenzylidene)triaminoguanidinium chloride [H6(OMe)3Br3L]Cl (5), leads to the formation of a doughnut-shaped, protein-sized coordination oligomer (Et3NH)18[{Zn[Zn2Cl{(OMe)3Br3L}]2}6(mu-Cl)6(OH2)6]x CH3CN (6), which comprises six dimeric [Zn5{(OMe)3Br3L}2] units. Whereas 3 and 4 decompose in DMSO solution, 6 is surprisingly stable in the same solvent.     

Thermodynamics and kinetics of glyoxal dimer formation: a computational study

Density functional theory (B3LYP//6-311+G) calculations including Poisson-Boltzmann implicit solvent were used to study the hydration of glyoxal and subsequent formation of dimeric species in solution. Our calculations show that the dioxolane ring dimer is the thermodynamic sink among all monomers and dimers with varying degrees of hydration. Although fully hydrated species are thermodynamically favored over their less hydrated counterparts, we find that a preliminary dehydration step precedes dimerization and ring closure. Ring closure of the open dimer monohydrate to the dioxolane ring dimer is kinetically favored over both hydration to the open dimer dihydrate and ring closure to form the dioxane ring dimer. The kinetic barriers for different geometric approaches for dimerization suggest an explanation why oligomerization stops after the formation of a dioxolane ring trimer as observed experimentally.     

Stereoelectronic Features of a Complex Ketene Dimerization Reaction

The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed.     

Conformationally constrained sequence designs to bias monomer-dimer equilibriums in TASP systems

We have designed template-assembled synthetic proteins (TASPs) with the intent of controlling their oligomeric state by stabilizing specific helical tertiary structures via histidine metal ion chelation or disulfide incorporation. In solution, cavitein Q4 was previously determined to interconvert between a four-helix bundle monomer and an eight-helix bundle dimer. In this paper, we show that judicious mutation of cavitein Q4 can stabilize either the monomeric parallel four-helix bundle or the dimeric antiparallel eight-helix bundle structure. Cavitein Q4-E3H, designed to be dimeric, is indeed biased toward dimerization as a result of incorporation of histidines. Moreover, the addition of nickel was found to further increase the association constant of dimerization. Similarly, a cavitein designed to stabilize the monomeric structure via histidine metal ion chelation (Q4-H) was found to favor a monomer in solution upon addition of nickel. Lastly, a cavitein intended to stabilize a monomeric structure via disulfide incorporation (Q4-C2) is reported. Surprisingly, this disulfide cavitein yielded two products upon oxidation suggesting disulfide formation both above the cavitand template and below may be possible. Nevertheless, the two disulfide caviteins were shown to exist as monomers as per their design.     

Solution structure, dimerization, and dynamics of a lipophilic alpha/3(10)-helical, C alpha-methylated peptide. Implications for folding of membrane proteins.

The solution structure and the dimerization behavior of the lipophilic, highly C(alpha)-methylated model peptide, mBrBz-Iva(1)-Val(2)-Iva(3)-(alphaMe)Val(4)-(alphaMe)Phe(5)-(alphaMe)Val(6)-Iva(7)-NHMe, was studied by NMR spectroscopy and molecular dynamics simulations. The conformational analysis resulted in a right-handed 3(10)/alpha-helical equilibrium fast on the NMR time scale with a slight preference for the alpha-helical conformation. The NOESY spectrum showed intermolecular NOEs due to an aggregation of the heptapeptide. In addition, temperature-dependent diffusion measurements were performed to calculate the hydrodynamic radius. All these findings are consistent with an antiparallel side-by-side dimerization. The structure of the dimeric peptide was calculated with a simulated annealing strategy. The lipophilic dimer is held together by favorable van der Waals interactions in the sense of a bulge fitting into a groove. The flexibility of the helical conformations concerning an alpha/3(10)-helical equilibrium is shown in a 3 ns molecular dynamics simulation of the resulting dimeric structure. Both overall helical structures of each monomer and the antiparallel mode of dimerization are stable. However, transitions were seen of several residues from a 3(10)-helical into an alpha-helical conformation and vice versa. Hence, this peptide represents a good model in which two often-discussed aspects of hierarchical transmembrane protein folding are present: i <-- i + 3 and i <-- i + 4 local H-bonding interactions cause a specific molecular shape which is then recognized as attractive by other surrounding structures.     

Calix[4]arene-based bis[2]catenanes: synthesis and chiral resolution

The exclusive formation of hydrogen-bonded dimers between tetraaryl and tetratosylurea calix[4]arenes has been used to prepare a series of ten "bisloop" tetraurea calix[4]arenes 3, in which adjacent phenylurea groups are covalently linked through alpha,omega-dioxyalkane chains. This dimerization with tetratosylurea 2 as template preorganizes the alkenyl residues of tetra(m-alkenyloxyphenyl) ureas 1 and enables their selective connection in high yield (up to 95 %) by olefin metathesis followed by hydrogenation. The "bisloop" calixarenes 3 also exclusively form heterodimers with 1. Thus, in a separated metathesis/hydrogenation sequence, a series of 14 cyclic bis[2]catenanes 4, in which two calix[4]arenes are connected through their wide rims by two pairs of interlocked rings (total size 29 to 41 atoms), were prepared in yields of up to 97 %. Optical resolution of these chiral bis[2]catenanes was studied by HPLC on chiral stationary phases. The single-crystal X-ray structure of one example (4(P,10)) confirmed the interlocking rings and revealed that the hydrogen-bonded dimeric capsule of the calix[4]arene can be "completely" opened.     

3-Cyclobutenyl-1,2-dione-substituted porphyrins. 2. A simple and general entry to quinone-porphyrin-porphyrin-quinone tetrads and related molecules

The synthesis of meso-linked quinone-porphyrin-porphyrin-quinone tetrads has been accomplished by the simple treatment of a CH2Cl2 solution of zincated 5-substituted-10,20-diphenylporphyrins (where the substituent = 3-cyclobutenyl-1,2-dione, various quinonyl derivatives, and p-anisyl) with 2,3-dichloro-5,6-dicyanoquinone (DDQ). The zincated porphyrinic quinones were synthesized from 5-(3-cyclobutenyl-1,2-dione)-10,20-diphenylporphyrin(Zn). The meso-linked dimer of 5-(3-cyclobutenyl-1,2-dione)-10,20-diphenylporphyrin(Zn) was also shown to be a useful precursor to meso-linked quinone-porphyrin-porphyrin-quinone tetrads. This DDQ-based oxidative dimerization appears to be general and effective for various zincated 5-substituted-10,20-diphenylporphyrins bearing both electron-withdrawing and -donating substituents. The oxidative dimerization was very sensitive to the reaction solvent (dimerization occurred in CH2Cl2, not in THF) and required the zincated porphyrins (the corresponding free base porphyrins did not undergo dimerization). When this solvent effect was applied to the reaction of I2/AgO2CCF3 with zincated porphyrins, either the dimeric porphyrins or iodoporphyrins could be selectively prepared simply by selecting methylene chloride or THF as the reaction solvent, respectively.     

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.     

Highly diastereoselective self-assembly of chiral tris(m-ureidobenzyl)amino capsules

The self-assembly of chiral tris(m-ureidobenzyl)amines to give dimeric capsules is a highly diastereoselective process in solution, while in the solid state, the formation of the corresponding capsules is not only diastereoselective but also regioselective.     

Tris(pyridylmethylamino)cyclotriguaiacylene cavitands: an investigation of the solution and solid-state behaviour of metallo-supramolecular cages and cavitand-based coordination polymers

The synthesis of the three isomeric tris(pyridylmethylamino)cyclotriguaiacylene cavitands is reported, along with the crystal structures of the 2- and 4-pyridyl derivatives. The generality of a previously described [Ag(2){tris(3-pyridylmethylamino)cyclotriguaiacylene}(2)](2+) dimeric capsule motif and the [Ag(4){tris(4-pyridylmethylamino)cyclotriguaiacylene}(4)](4+) tetrahedron with several silver salts was confirmed in the solid state and the corresponding solution species were investigated by NMR spectroscopy. Host-guest interactions in these systems have been probed and these interactions are demonstrated to alter and influence the self-assembly outcome of the reaction. Notably, introduction of larger glutaronitrile guest molecules to the [Ag(4)L(4)](4+) tetrahedron system prevents formation of the tetrahedral structure, resulting instead in the formation of a 4.8(2) coordination network in the solid state. In the absence of templating acetonitrile guests in the [Ag(2)(3)(2)](2+) capsule system, formation of a cage-based one-dimensional coordination polymer is observed.     

Tris(trimethylsilyl)silylamin und seine lithiierten und silylierten Derivate — Kristallstruktur des dimeren Lithium-trimethylsilyl-[tris(trimethylsilyl)silyl]amids

Tris(trimethylsilyl)silylamine and the lithiated and silylated Derivatives — X-Ray Structure of the dimeric Lithium Trimethylsilyl-[tris(trimethylsilyl)silyl]amide The ammonolysis of the chlor, brom or trifluormethanesulfonyl tris(trimethylsilyl)silane yields the colorless tris(trimethylsilyl)silylamine, destillable at 51°C and 0.02 Torr. The subsequent lithiation, reaction with chlor trimethylsilane and repeated lithiation lead to the formation of lithium tris(trimethylsilyl)silylamide, trimethylsilyl-[tris(trimethylsilyl)silyl]amine and finally lithium trimethylsilyl-[tris(trimethylsilyl)silyl]amide, which crystallizes in the monoclinic space group P2₁/n with a = 1 386.7(2); b = 2 040.2(3); c = 1 609.6(2) pm; β = 96.95(1)° and Z = 4 dimeric molecules. The cyclic Li₂N₂ moiety with Li? N bond distances displays a short transannular Li …? Li contact of 229 pm. The dimeric molecule shows nearly C₂-symmetry, so that one lithium atom forms agostic bonds to both the trimethylsilyl groups, the other one to the tris(trimethylsilyl)silyl substituents. However, the ⁷Li{¹H}-NMR spectrum displays a high field shifted singlet at —1.71 ppm. The lithiation of trimethylsilyl-[tris(trimethylsilyl)silyl]amine leads to a high field shift of the ²⁹Si{¹H} resonance of about 12 ppm for the Me₃SiN group, whereas the parameters of the tris(trimethylsilyl)silyl ligand remain nearly unaffected.     

Steric stabilization of a monomeric proalumatrane: experimental and theoretical studies

Treatment of tripodal tris(3-tert-butyl-2-hydroxy-5-methylbenzyl)amine (L) with 1 equiv of trimethylaluminum in toluene gave the stable proalumatrane (AlL) (1) [wherein L = tris(3-tert-butyl-5-methyl-2-oxidobenzyl)amine] featuring a distorted trigonal monopyramidal four-coordinate aluminum geometry. An analogous reaction uses the less sterically congested isomer of L, namely, tris(5-tert-butyl-2-hydroxy-3-methylbenzyl)amine provided dimeric (AlL')2 (2) [wherein L' = tris(5-tert-butyl-3-methyl-2-oxidobenzyl)amine], which contains two bridging alumatrane moieties possessing five-coordinate TBP aluminum geometries. Reaction of AlL with water provided the adduct H2O.AlL (3), a species that is representative of a coordinatively stabilized intermediate in the hydrolysis of an aluminum alkoxide. Theoretical calculations revealed that considerable stabilization energy is obtained by the coordination of a water molecule to the tetracoordinate aluminum in AlL and that this result is consistent with the postulate that the Lewis acidity of AlL exceeds that of boron trifluoride, despite the presence of the transannular N-->Al bond in AlL.     

The dimeric "hand-shake" motif in complexes and metallo-supramolecular assemblies of cyclotriveratrylene-based ligands

A series of clathrate and metal complexes with cyclotriveratrylene-like molecular host ligands show a similar dimeric homomeric inclusion motif in which a ligand arm of one host is the intra-cavity guest of another and vice versa. This "hand-shake" motif is found in the trinuclear transition metal complex [Cu(3)Cl(6)(1)]CH(3)CN1.5 H(2)O in which 1 is tris(4-[2,2',6',2'-terpyridyl]benzyl)cyclotriguaiacylene; in the self-included M(4)L(4) tetrahedral metallo-supramolecular assembly [Ag(4)(2)(4)] (BF(4))(4) in which 2 is tris-(2-quinolylmethyl)cyclotriguaiacylene; in the 1D coordination chains [Ag(4)]ReO(4) CH(3)CN and [Ag(5)]SbF(6)3 DMFH(2)O in which 4 is tris(1H-imidazol-1-yl)cyclotriguaiacylene and 5 is tris{4-(2-pyridyl)benzyl}cyclotriguaiacylene; and in the acetone clathrate of tris{4-(2-pyridyl)benzyl-amino}cyclotriguaiacylene. Clathrates of ligands 2 and 5 do not show the same dimeric motif, although 2 has an extended homomeric inclusion motif that gives a hexagonal network.     

A novel transformation of a zirconium imido compound and the development of a new class of N3 donor heteroscorpionate ligand

Reaction of the dimeric zirconium imido compound [Zr2(mu-NAr)2Cl4(THF)4] with tris(3,5-dimethylpyrazolyl)methyl silane very selectively gave [Zr{(Me2pz)2Si(Me)NAr}Cl3] (1), a highly active pre-catalyst for ethylene polymerisation; a more general and versatile route to N3 donor heteroscorpionate compounds was achieved via the protio ligand (Me2pz)2CHSi(Me)2N(H)iPr for which neutral and cationic organometallic Group 3 and 4 derivatives are reported (Ar = 2,6-C6H(3)iPr2).     

Complexation-induced unfolding of heterocyclic ureas. Simple foldamers equilibrate with multiply hydrogen-bonded sheetlike structures.

The synthesis and conformational studies of heterocyclic ureas (amides) 1-7 and their concentration-dependent unfolding to form multiply hydrogen-bonded complexes are described. Ureas 1 and 7 were prepared by reacting 2-aminopyridine and aminonaphthyridine 25, respectively, with triphosgene and 4-(dimethylamino)pyridine (DMAP). Amine 25, in turn, was synthesized by a Knorr condensation of 2,6-diaminopyridine and 4,6-nonanedione. Heterocyclic ureas 3, 4, and 16 were prepared by treating their corresponding amino precursors with butylisocyanate, whereas bisureido naphthyridines 6 and 17 were prepared by heating 2,7-diamino-1,8-naphthyridine (13) with butylisocyanate and 3,4,5-tridodecyloxyphenyl isocyanate, respectively. The hydrogen-bonding modules 2 and 5 were synthesized by reacting 13 and 2-amino-1,8-naphthyridine with valeric anhydride. X-ray crystallographic analyses were performed on ureas 1, 3, 16, and 17, indicating that these ureas are intramolecularly hydrogen-bonded in the solid state. Moreover, detailed 1H NMR solution studies of 1, 3, 4, 6, and 7 indicate that similar folded structures form in chloroform. In addition, naphthyridinylureas 3 and 7 unfold and dimerize by forming four hydrogen bonds at high concentrations, and ureas 1 and 4 unfold in the presence of their hydrogen-bonding complements, amides 2 and 5, to form complexes with three and four hydrogen bonds, respectively. Likewise, the mixing of 6 and 7 results in a mutual unfolding and formation of a robust, sheetlike, sextuply hydrogen-bonded complex. The hydrogen-bonding modules described are useful building blocks for self-assembly, and the unfolding process represents a very primitive mimicry of the helix-to-sheet transition shown by peptides and potentially shown by the hypothetical naphthyridinylurea 8.     

Schiff base route to stackable pseudo-triphenylenes: stereoelectronic control of assembly and luminescence

Tandem tautomerization-trapping of isomeric mixtures of tris(N-salicylideneamine)s facilitated access to a new class of discotic molecules that are geometrically analogous to 2,6,10-trisubstituted triphenylenes. The shape and electrostatic complementarity associated with the molecular C3 symmetry assists cofacial stacking of pi-faces to afford either infinite one-dimensional columns or discrete dimeric capsules. Structural reinforcement achieved by such interlocked geometry resulted in significant fluorescence enhancement upon aggregation in solution, as determined by dynamic light scattering and fluorescence spectroscopy.     

Oxyanion-encapsulated caged supramolecular frameworks of a tris(urea) receptor: evidence of hydroxide- and fluoride-ion-induced fixation of atmospheric CO2 as a trapped CO3(2-) anion

A tris(2-aminoethyl)amine-based tris(urea) receptor, L, with electron-withdrawing m-nitrophenyl terminals has been established as a potential system that can efficiently capture and fix atmospheric CO(2) as air-stable crystals of a CO(3)(2-)-encapsulated molecular capsule (complex 1), triggered by the presence of n-tetrabutylammonium hydroxide/fluoride in a dimethyl sulfoxide solution of L. Additionally, L in the presence of excess HSO(4)(-) has been found to encapsulate a divalent sulfate anion (SO(4)(2-)) within a dimeric capsular assembly of the receptor (complex 2) via hydrogen-bonding-activated proton transfer between the free and bound HSO(4)(-) anions. Crystallographic results show proof of oxyanion encapsulation within the centrosymmetric cage of L via multiple N-H···O hydrogen bonds to the six urea functions of two inversion-symmetric molecules. The solution-state binding and encapsulation of oxyanions by N-H···O hydrogen bonding has also been confirmed by quantitative (1)H NMR titration experiments, 2D NOESY NMR experiments, and Fourier transform IR analyses of the isolated crystals of the complexes that show huge spectral changes relative to the free receptor.     

Dual Association Modes of the 2,5,8‐Tris(pentafluorophenyl)phenalenyl Radical

The 2,5,8‐tris(pentafluorophenyl)phenalenyl radical was obtained by a straightforward synthesis in 11 steps from 2,7‐dibromonaphthalene. This radical crystallized as a σ dimer from a solution in MeCN and as a π‐stack from a melted liquid. The π stack was not confined to dimerization, but extended into a uniform 1D stack with an interplanar distance of 3.503 Å. This unique duality in association mode arose from the thermodynamic stability of the phenalenyl moiety.