Structure and dynamics of some macrocyclic pyrimidine derivatives

The conformation of macrocycles consisting of the uracil and two thiopyrimidine moieties linked by polymethylene spacers depends on the spacer length, intramolecular hydrogen bonds, and the solvent nature. In CDCl₃ the intramolecular hydrogen bond (NH) appreciably stabilizes the “skew” conformation but only for the macrocycles with methylene spacers consisting of five carbon atoms. Protonation leads to the cleavage of intramolecular hydrogen bonds, destabilization of the “skew” conformation, and self-association due to the strong intermolecular hydrogen bond involving the acid counterion, and the intermolecular bond is cleaved in a polar solvent.     

Shape selectivity in the synthesis of chiral macrocyclic amides

Shape-persistent, optically-active arylamide macrocycles have been designed and approached by using a stepwise, convergent methodology. The source of chirality, an axially-chiral Binol scaffold, incorporates methoxy functionalities in the 2,2′ positions, and carboxylic functionalities in the external 3,3′ positions. The latter can be efficiently elaborated through aromatic amidation to introduce aromatic spacers of differing shapes. The peculiar arrangement of functionalities on the Binol skeleton functions as an element of rigidification of the covalent structure through the formation of stable intramolecular hydrogen bonds. When this element is counterbalanced by the use of a flexible 3,3′-diaminobiphenyl as a spacer, yields for the macrocyclization step increase to values higher than 50%. The recognition properties of this particular macrocycle have been exploited and, while they indicate modest binding affinities towards carboxylate anions, the additional stabilization of neighbouring amide functionalities suitably placed within the covalent framework induces detectable binding of proper difunctional carboxylates.     

Cyclic tetraureas with variable flexibility--synthesis, crystal structures and properties

Macrocyclic molecules containing several amide or urea functions may serve as anion receptors. We describe the synthesis of 32-membered macrocycles, in which four rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All six possible combinations of these units (XXXX, XXXD, XXDD, XDXD, XDDD and DDDD) were synthesized and two examples were characterised by single-crystal X-ray analyses (DDDD and two structures for XXXD). Both macrocycles showed distinct differences in their overall conformation and consequently in their hydrogen-bonding pattern. Hydrogen-bonded solvent molecules are found for both compounds and intramolecular hydrogen bonds for the two structures of XXXD, but surprisingly no direct intermolecular hydrogen bonds between the macrocyclic tetraurea molecules. The interaction with various anions was studied by (1)H NMR spectroscopy. Stability constants for all tetramers were determined by UV spectroscopy for complexes with chloride, bromide, acetate and dihydrogenphosphate in acetonitrile-THF (3:1). The strongest binding was found for XXXD and acetate (log beta = 7.4 +/- 0.2), the weakest for XXXX and acetate (log beta = 5.1 +/- 0.5). MD simulations in chloroform and acetonitrile boxes show that all molecules except DDDD adopt very similar conformations characterized by an up-down-up-down arrangement of the spacer groups. Clustered solvation shells of acetonitrile molecules around XXXX and DDDD suggest their preorganization for spherical/planar and tetrahedral/bidentate anions, respectively, which in turn was corroborated by simulation of the corresponding complexes with chloride and dihydrogenphosphate.     

Aza-crown macrocycles as chiral solvating agents for mandelic acid derivatives

A series of new chiral macrocycles containing the trans-1,2-diaminocyclohexane (DACH) subunit and arene- and oligoethylene glycol-derived spacers has been prepared in enantiomerically pure form. Four of the macrocycles have been characterized by X-ray crystallography, which reveals a consistent mode of intramolecular N-H···N hydrogen bonding and conformational variations about the N-benzylic bonds. Most of the macrocycles were found to differentiate the enantiomers of mandelic acid (MA) by (1)H NMR spectroscopy in CDCl(3); within the series of macrocycles tested, enantiodiscrimination was promoted by (i) a meta-linkage geometry about the arene spacer, (ii) the presence of naphthalene- rather than phenylene-derived arene spacers, and (iii) increasing length of the oligoethylene glycol bridge. (1)H NMR titrations were performed with optically pure MA samples, and the data were fitted to a simultaneous 1:1 and 2:1 binding model, yielding estimates of 2:1 binding constants between some of the macrocycles and MA enantiomers. In several cases, NOESY spectra of the MA:macrocycle complexes show differential intramolecular correlations between protons adjacent to the amine and carboxylic acid groups of the macrocycles and MA enantiomers, respectively, thus demonstrating geometric differences between the diastereomeric intermolecular complexes. The three most effective macrocycles were employed as chiral solvating agents (CSAs) to determine the enantiomeric excess (ee) of 18 MA samples over a wide ee range and with very high accuracy (1% absolute error).     

Conformational control of selectivity and stability in hybrid amide/urea macrocycles

The anion-binding properties of two similar hybrid amide/urea macrocycles containing either a 2,6-dicarboxamidophenyl or a 2,6-dicarboxamidopyridine group are compared. Significant differences in anion affinity and mode of interaction with anions are attributed to the presence of intramolecular hydrogen bonds in the pyridine system. In fact, remarkably, the phenyl macrocycle undergoes amide hydrolysis under neutral conditions in DMSO/water. The anion binding abilities of the receptors are compared to those of acyclic analogues of the macrocycles that show that the phenyl receptor behaves in a similar fashion to acyclic urea-containing receptors (i.e., showing little selectivity amongst oxo anions), whilst the pyridine-containing receptor shows a high affinity and selectivity for carboxylates.     

Effects of hydrogen bonding on metal ion-promoted intramolecular electron transfer and photoinduced electron transfer in a ferrocene-quinone dyad with a rigid amide spacer

A ferrocene-quinone dyad (Fc-Q) with a rigid amide spacer and Fc-(Me)Q dyad, in which the amide proton acting as a hydrogen-bonding acceptor is replaced by the methyl group, are employed to examine the effects of hydrogen bonding on both the thermal and the photoinduced electron-transfer reactions. The hydrogen bonding of the semiquinone radical anion with the amide proton in Fc-Q(.-) produced by the electron-transfer reduction of Fc-Q is indicated by the significant positive shift of the one-electron reduction potential of Fc-Q. The hyperfine coupling constants of Fc-Q(.-) also indicate the existence of hydrogen bonding, agreeing with those predicted by the density functional calculation. The hydrogen-bonding dynamics in the photoinduced electron transfer from the ferrocene (Fc) to the quinone moiety (Q) in Fc-Q have been successfully detected in the femtosecond laser flash photolysis experiments. Thermal intramolecular electron transfer from Fc to Q in Fc-Q and Fc-(Me)Q also occurs efficiently in the presence of metal ions in acetonitrile at 298 K. The hydrogen bond formed between the semiquinone radical anion and the amide proton in Fc-Q results in remarkable acceleration of the rate of metal ion-promoted electron transfer as compared to the rate of Fc-(Me)Q in which hydrogen bonding is prohibited. The metal ion-promoted electron-transfer rates are well correlated with the binding energies of superoxide ion-metal ion complexes, which are derived from the g(zz) values of the ESR spectra.     

Multivalent macrocyclic hosts: histone surface recognition, guest binding, and delivery by cyclophane-based resorcinarene oligomers

As a new class of host for both specific proteins and hydrophobic molecular guests, cyclophane-based resorcinarene oligomers were designed on the basis of a molecular design that allows the assembly of four or 12 anionic resorcinarenes on a cyclophane skeleton. We prepared a cyclophane-based resorcinarene tetramer (4), constructed with a tetraaza[6.1.6.1]-paracyclophane skeleton and four resorcinarenes bearing heptacarboxylic acid residues that connect to the macrocycle through amide linkages. In addition, we prepared an extended analogical dodecamer (12), which was constructed with a pentakis(cyclophane) skeleton and 12 resorcinarenes. The cyclophane-based resorcinarene oligomers exhibited potent recognition capabilities toward histone, a small basic protein of eukaryotic chromatins. The binding constants (K) of cyclophane-based resorcinarene tetramer 4 and dodecamer 12 with histone were determined to be 1.3x107 and 8.4x107 M-1, respectively, by means of surface plasmon resonance measurements. The K values of 4 and 12 with histone were 31- and 200-fold larger than that of an untethered reference resorcinarene, reflecting the multivalency effects in resorcinarenes. In addition to that, cyclophane-based resorcinarene tetramer 4 and dodecamer 12 captured hydrophobic guests such as 6-p-toluidinonaphthalene-2-sulfonate, with respective binding constants of 2.4x103 and 2.5x104 M-1 in an aqueous HEPES buffer as evaluated by fluorescence spectroscopy. Furthermore, the resorcinarene oligomers were also found to act as guest carriers from the bulk aqueous phase to histone surfaces, as confirmed by fluorescence spectroscopy.     

Properties of ionic liquids containing silver(I) or protic alkylethylenediamine cations with a bis(trifluoromethanesulfonyl)amide anion

Ionic liquids of an N-alkylethylenediamine-silver(I) complex cation (alkyl=hexyl, 2-ethylhexyl, and octyl) or a protic N-alkylethylenediaminium cation (alkyl=butyl, hexyl, 2-ethylhexyl, octyl, decyl, and dodecyl) with a bis(trifluoromethanesulfonyl)amide counter anion (Ag-ILs and PILs, respectively) were prepared and their physicochemical properties were investigated. The trend of solidification decreased in the order octyl?hexyl>2-ethylhexyl for the Ag-ILs, and butyl>dodecyl>decyl>octyl>hexyl?2-ethylhexyl for the PILs. The diffusion coefficients of the cations indicated stronger intermolecular interactions in PILs than in the Ag-ILs because of hydrogen-bonding networks, and it has been revealed that the intermolecular interactions increase in the order, hexyl相似文献   

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.     

Ortho-substituted catechol derivatives: the effect of intramolecular hydrogen-bonding pathways on chloride anion recognition

This paper reports a series of chloride anion receptors containing two catechol head groups connected through their ortho-positions via a spacer chain. The linking group chosen to attach the spacer chain to the catechol units has a major impact on the anion-binding potential of the receptor. Linking groups that are capable of forming stable six-membered intramolecular hydrogen-bonded rings with the catechol O-H groups significantly inhibit the ability of the catechol units to hydrogen bond to chloride anions. However, where the linking groups are only capable of forming five- or seven-membered intramolecular hydrogen-bonded rings, then anion binding via hydrogen bonding through the catechol O-H groups becomes a possibility. This process is solvent dependent; the presence of competitive solvent (e.g., DMSO-d6) disrupts the intramolecular hydrogen-bonding pattern and enhances anion binding relative to simple unfunctionalized catechol. The most effective receptor is that in which the hydrogen-bonding linker (-CH2CONH-) is most distant from the catechol units and can only form a seven-membered intramolecular hydrogen-bonded ring. In this case, the receptor, which contains two catechol units, is a more effective chloride anion binder than simple unfunctionalized catechol, demonstrating that the two head groups, in combination with the N-H groups in the linker, act cooperatively and enhance the degree of anion binding. In summary, this paper provides insight into the hydrogen-bonding patterns in ortho-functionalized catechols and the impact these have on the potential of the catechol O-H groups to hydrogen bond to a chloride anion.     

Structure and dynamics of pyrimidine-based macrocycles in solution

The conformational structure of macrocycles obtained from two thiopyrimidine and uracil nucleic acids linked by polymethylene spacers is determined by the length of the spacers, intramolecular NH bonding, pH and solvent. In CDCl₃, NH-OC hydrogen bonding can impact the overall stabilization of the folded conformation, however spatial preorganization to such hydrogen bonding is a prerequisite. Protonation leads to disruption of intramolecular hydrogen bonds, destabilization of the folded conformation and to strong counterion assisted self-aggregation of macrocyles which can be destroyed in polar solvents.     

Cyclic triureas--synthesis, crystal structures and properties

The synthesis of 24-membered macrocycles is described, in which rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All four possible combinations (XXX, XXD, XDD, DDD) have been obtained with yields of 40-72% for the cyclisation step. In two cases, the respective cyclic hexamers (XXDXXD, XXXXXX) were also isolated. Two compounds have been characterised by a single crystal X-ray analysis of the free triurea (XXD, XDD) and one example (DDD) by its complex with tetrabutylammonium chloride. It shows the chloride anion in the centre of the macrocycle, held by six NH...Cl- hydrogen bonds. The interaction with various other anions has been studied by 1H NMR. Complexation constants for chloride, bromide and acetate have been measured for all trimers by UV spectrophotometry. Molecular dynamics simulations have been carried out to determine the conformation of the free receptors in chloroform and acetonitrile. They show that in chloroform, intramolecular hydrogen bonding occasionally facilitated by trans-->cis isomerisation of an amide bond dominates the conformation of the macrocycles while in acetonitrile (the solvent used for complexation measurements), the ligating urea NH protons are properly arranged for the complexation of anions, however, their strong solvation is counteractive to the complexation.     

Designing hybrid foldamers: the effect on the peptide conformational bias of β- versus α- and γ-linear residues in alternation with (1R,2S)-2-aminocyclobutane-1-carboxylic acid

Several oligomers constructed with (1R,2S)-2-aminocyclobutane-1-carboxylic acid and glycine, β-alanine, and γ-amino butyric acid (GABA), respectively, joined in alternation have been synthesized and studied by means of NMR and CD experiments as well as with computational calculations. Results account for the spacer length effect on folding and show that conformational preference for these hybrid peptides can be tuned from β-sheet-like folding for those containing a C(2) or C(4) linear segment to a helical folding for those with a C(3) spacer between cyclobutane residues. The introduction of cyclic spacers between these residues does not modify the extended ribbon-type structure previously manifested in poly(cis-cyclobutane) β-oligomers.     

手性氨基醇诱导联苯构象转化制备轴手性联苯化合物

在(S)-氨基丙醇及(R)-氨基丙醇手性臂的作用下, (M/P)-4,4'-二甲氧基-5,6,5',6'-二次甲二氧基-2-甲酸酯-2'-甲酰氨联苯经构型转化, 制备了光学纯轴手性联苯化合物(P, S)-3a 和(M, R)-3a. 测定了(P, S)-3a 的晶体结构及CD 光谱. 结果表明, 化合物(P, S)-3a 晶体属单斜晶系, P2(1)空间群, 晶胞参数为a＝12.122(2) Å, b＝8.9911(18) Å, c＝12.779(3) Å, β＝112.38(3)°, 在晶体中存在两组分子间氢键相互作用, 一组氢键由羟基氢与另一分子酰胺基团的羰基氧组成O-H…O,另一组由酰胺基团的NH 与另一分子酰胺基团的羰基氧构成N-H…O, 每一分子通过四个氢键与另外两个分子相连,构成棒状结构. 由CD 光谱确定了(M, R)-3b 的立体构型. 此外, 由(P, S)-3a 合成了轴手性化合物(P)-2,2'-二羟甲基-4,4'-二甲氧基-5,6,5',6'-二亚甲二氧基-联苯(6a).     

L-lysine based gemini organogelators: their organogelation properties and thermally stable organogels

Novel gemini organogelators based on L-lysine, in which two L-lysine derivatives are linked by different alkylene chain lengths through the amide bond, have been simply and effectively synthesized, and their organogelation abilities and thermal stabilities have been investigated. In a series of L-lysine ethyl ester derivatives, the organogelation abilities decreased with increasing alkylene spacer length. In particular, bis(N(epsilon)-lauroyl-L-lysine ethyl ester) oxalyl amide is a good organogelator that gels most organic solvents such as alcohols, cyclic ethers, aromatic solvents and acetonitrile. Various oxalyl amide derivatives with different alkyl ester groups such as hexyl, decyl, dodecyl, 2-ethyl-1-hexyl and 3,5,5-trimethylhexyl also showed good organogelation abilities. Furthermore, it was found that the cyclohexane gels formed by some oxalyl amide derivatives have a high thermal stability.     

Hydrogen-bonded aryl amide macrocycles: synthesis, single-crystal structures, and stacking interactions with fullerenes and coronene

Six hydrogen-bonded shape-persistent aryl amide macrocycles have been prepared by using one-step and (for some) step-by-step approaches. From the one-step reactions, 3 + 3, 2 + 2, or even 1 + 1 macrocycles were obtained in modest to good yields. The reaction selectivity was highly dependent on the structures of the precursors. The X-ray structural analysis of two methoxyl-bearing macrocycles revealed intramolecular hydrogen bonding and weak intermolecular stacking interaction; no column-styled stacking structures were observed. The 1H (DOSY) NMR, UV-vis, and fluorescent experiments indicated that the new rigidified macrocycles complex fullerenes or coronene in chloroform through intermolecular pi-stacking interaction. The association constants of the corresponding 1:1 complexes have been determined if the stacking was able to cause important fluorescent quenching of the macrocycles or coronene.     

Hydrogen-bonding cooperativity: using an intramolecular hydrogen bond to design a carbohydrate derivative with a cooperative hydrogen-bond donor centre

Neighbouring groups can be strategically located to polarise HO.OH intramolecular hydrogen bonds in an intended direction. A group with a unique hydrogen-bond donor or acceptor character, located at hydrogen-bonding distance to a particular OH group, has been used to initiate the hydrogen-bond network and to polarise a HO.OH hydrogen bond in a predicted direction. This enhanced the donor character of a particular OH group and made it a cooperative hydrogen-bond centre. We have proved that a five-membered-ring intramolecular hydrogen bond established between an amide NH group and a hydroxy group (1,2-e,a), which is additionally located in a 1,3-cis-diaxial relationship to a second hydroxy group, can be used to select a unique direction on the six-membered-ring intramolecular hydrogen bond between the two axial OH groups, so that one of them behaves as an efficient cooperative donor. Talose derivative 3 was designed and synthesised to prove this hydrogen-bonding network by NMR spectroscopy, and the mannopyranoside derivatives 1 and 2 were used as models to demonstrate the presence in solution of the 1,2-(e,a)/five-membered-ring intramolecular hydrogen bond. Once a well-defined hydrogen-bond is formed between the OH and the amido groups of a pyranose ring, these hydrogen-bonding groups no longer act as independent hydrogen-bonding centres, but as hydrogen-bonding arrays. This introduces a new perspective on the properties of carbohydrate OH groups and it is important for the de novo design of molecular recognition processes, at least in nonpolar media. Carbohydrates 1-3 have shown to be efficient phosphate binders in nonpolar solvents owing to the presence of cooperative hydroxy centres in the molecule.     

Double-helical cyclic peptides: design, synthesis, and crystal structure of figure-eight mirror-image conformers of adamantane-constrained cystine-containing cyclic peptide cyclo (Adm-Cyst)(3)

A large number of macrocycles containing alternating repeats of cystine diOMe(-NH-CH(CO(2)Me)-CH(2)-S-)(2) and either a conformationally rigid aromatic/alicyclic moiety or a flexible polymethylene unit (X) in the cyclic backbone with ring size varying from 13- to 78-membered have been examined by spectral ((1)H NMR, FT-IR, CD) and X-ray crystallography studies for unusual conformational preferences. While (1)H NMR measurements indicated a turnlike conformation for all macrocycles, stabilized by intramolecular NH.CO hydrogen bonding, as also supported by FT-IR spectra in chloroform, convincing proof for beta-turn structures was provided by circular dichroism studies. Single-crystal X-ray studies on 39-membered cyclo (Adm-L-Cyst)(3) revealed a double-helical fold (figure-eight motif) for the macrocycle. Only a right-handed double helix was seen in the macrocycle constructed from L-cystine. The mirror-image macrocycle made up of D-cystine units exhibited a double helix with exactly the opposite screw sense, as expected. The enantiomeric figure-eights were stabilized by two intramolecular NH. CO hydrogen bonds and exhibited identical (1) H NMR and FT-IR spectra. The CD spectra of both isomers had a mirror-image relationship. The present results have clearly brought out the importance of cystine residues in inducing turn conformation that may be an important deciding factor for the adoption of topologically important structures by macrocycles containing multiple S-S linkages.     

Contribution of intramolecular C=O...H-N hydrogen bonding to the solvent-induced reentrant phase separation of poly(N-isopropylacrylamide)

Changes in the local environment around amide groups of poly(N-isopropylacrylamide) (PNiPA) during a solvent-induced reentrant phase separation have been investigated by infrared spectroscopy combined with quantum chemical calculations. The addition of methanol or tetrahydrofuran as a cosolvent to an aqueous solution of PNiPA causes spectral changes in the amide I regions. By preparing a dimer model compound for PNiPA, we can establish the assignment of the amide I bands for the polymer in solutions. Hydrogen-deuterium exchange experiments of the amide protons of PNiPA and its dimer models have revealed that the amide groups of PNiPA form an intramolecular C=O...H-N hydrogen bond even in a good solvent. The result has suggested that the change in the amide I envelope of PNiPA observed during the solvent-induced phase transition reflects the modification of the intramolecular C=O...H-N hydrogen bond of PNiPA as well as the variation in solvation state of the amide groups. On the basis of the assignment, we have discussed contributions of the intramolecular C=O...H-N hydrogen bond to the phase behavior of PNiPA.     

Biodegradable gemini surfactants. Correlation of area per surfactant molecule with surfactant structure

Values of the area per surfactant molecule of various single chain and gemini quaternary ammonium surfactants containing biodegradable amide and ester groups are obtained from the surface tension measurements and they are mutually compared. It was found that surfactant molecules with the ester group in their structure occupy smaller area at the air/water interface than the corresponding molecules with the amide group, mainly due to the higher conformational flexibility of ester groups. In decreasing the area per surfactant molecule value, hydrogen bonding (both inter- and intramolecular) plays a significant role when amide groups are present in the spacer of a gemini molecule. They must be separated by a polymethylene chain or a flexible group such as cyclohexane which is short enough to allow intramolecular hydrogen bonds. The flexible cyclohexane group with the amide group in single chain surfactants may lead to the formation of intermolecular hydrogen bonds among surfactant molecules which also results in the reduction of the area per surfactant molecule.