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Hypothesis Sodium deoxycholate is a natural bile salt produced by animals and fulfilling important physiological processes. It is also used as dispersive surfactant and building block for self-assembled architectures in biology and material science. Although long debated, the study of its self-assembly in water is hereto incomplete and the models of the known aggregates are still controversial. This background suggests a complex scenario likely missing of additional mesophases. Experiments Electron and optical microscopy techniques were crossed with SAXS data for the research. Findings Novel rod, sponge, vesicle, lamellae, nanotube phases and reversible transitions among them arise at conditions (concentration, pH, temperature, ionic strength, ionic composition) fitting the physiological working environment of sodium deoxycholate. These findings enlarge the perspective towards different directions. The integration of the previous literature with this work removes any interpretative contradiction since all the structures cover the entire spectrum of phases expected for surfactants, thus being explained according to the Israelachvili’s scheme. It is not trivial that a single molecule can show such a high structural variability. This fact highlights a very versatile system. Probably it is not a coincidence that it occurs in a multitasking biomolecule. These results furnish fundamental knowledge to clarify the bile salts’ role in vivo.

The crystal structure of the iodide salt of a quaternary ammonium derivative of cholic acid having a naphthalene group attached to the 3rd position of the steroid nucleus through an amide bond ([3,5,7,12]-3-(2-naphthyloylamino)-7,12-dihydroxycholan-24-triethylammonium iodide) has been resolved. The compound crystallizes in the P212121 orthorhombic space group (a/Å = 10.9458(3), b/Å = 12.1625(3), c/Å = 28.4706(7)). The lateral chain adopts a fully extended tttt conformation because the quaternary ammonium group cannot participate in the formation of hydrogen bonds. The iodide ion is involved in the formation of hydrogen bonds as well as the amide group and the two steroid hydroxy groups. Hirshfeld surface analysis confirms that these contacts, as well as the electrostatic interactions, stabilize the structure. The helixes around the 21 screw axis are right-handed ones.

A complete characterization of the aggregation process of the sodium salts of chenodeoxycholic (NaCDC) and obeticholic (NaObC) acids has been carried out by using different experimental techniques. Since it is well known that the presence of hydrophobic groups strongly reduce the critical aggregation concentrations and modifies the type of aggregation structures which can be formed, it could be expected that the introduction of an ethyl group into the structure of the chenodeoxycholic acid, to form the obeticholic derivative, could give rise to important modifications in its aggregation behavior. However, it has been observed that the aggregation numbers (determined in the range of temperatures 10–40 °C from ITC measurements) are identical to each other, a fact which was supported by the determination of the hydrodynamic radius from dynamic light scattering. This similarity was also observed for the fraction of bound counterions determined from the well-known Corrin–Harkins plot, being equal to 0.33 for both compounds. Finally, the polarity of the interior of the aggregate as measured by the ratio of the fluorescence intensities of the first and third vibronic peaks, I1/I3, of monomeric pyrene solubilized within the aggregates is also identical within the experimental error. The main differences correspond to: (1) the temperatures at which the enthalpy of demicellization is zero (31.4 (NaObC) and 26.8 °C (NaCDC)); and (2) the cmc value for NaObC is roughly half the one for NaCDC as observed from surface tension, fluorescence and ITC measurements. This implies that the free energy for the demicellization process is around 2 kJ mol−1 larger for NaObC than for NaCDC. (3) Finally, the difference in the change in the heat capacity of the aggregation (being 60 J mol−1 K−1 higher for ObCA) is due to the different number of water molecules which are lost during the monomer transfer from the bulk solution to the micellar aggregate.

The crystal structures of two ester compounds (a monomer in its methyl ester form,with anamino isophthalic group, and a dimer in which the two steroid units are linked by a urea bridgerecrystallized from ethyl acetate/methanol) derived from cholic acid are described. Average bondlengths and bond angles from the crystal structures of 26 monomers and four dimers (some of themin several solvents) of bile acids and esters (and derivatives) are used for proposing a standardsteroid nucleus. The hydrogen bond network and conformation of the lateral chain are also discussed.This standardstructure was used to compare with the structures of both progesterone and cholesterol The authors thank the Ministerio de Ciencia y Tecnología (Project MAT2013-45657-P) forfinancial support SI

The actual significance of the so-called compensation temperature Tc for micellization of surfactants is reviewed. It is demonstrated that it is possible to obtain as many Tc values as the number of temperature intervals in which the dependencies of enthalpy and entropy changes with temperature are analyzed. The value of each Tc will be the central value To of each temperature interval. These two facts suggest that Tc is simply such experimental To. Thus any physical interpretation derived from Tc is unfounded.

This work reports on the multi stimuli sensitivity of a cholic acid derivative in a buffer. The molecules self-organize in single walled tubules at room temperature and pH 8.0–9.5. By increasing the pH to 10.0–12.0, these tubules open up and form scrolls, which transform by aging into different tubular structures. A further evolution from scrolls or tubules into ribbons is induced by increasing the temperature. Moreover, a transition into rolled lamellae can be triggered by adding NaCl. All transitions are reversible and accompanied by drastic molecular rearrangements, manifested by spectroscopic and imaging techniques. Such rich multi stimuli responsiveness is usually accomplished by block copolymers or peptides and seldom by pure surfactants. The reported surfactant provides in addition an uncommon variety of structures. The sharpness of the spectroscopic response suggests that the system could be employed in physico-chemical sensors with a rather narrow dynamic range.

The compounds presented here constitute a clear example of molecular biomimetics as their design is inspired on the structure and properties of natural phospholipids. Thus novel double-armed surfactants have been obtained in which nitrilotriacetic acid plays the role of glycerol in phospholipids. The hydrophobic arms are linked to the head group through amide bonds (which is also the case of sphingomyelin): (R 1 NHCOCH 2 )(R 2 NHCOCH 2 ) NCH 2 CO 2 H (R 1 being CH 3 (CH 2 ) 11 , CH 3 (CH 2 ) 17 , CH 3 (CH 2 ) 7 CH CH(CH 2 ) 8 , and adamantyl, and R 2 = adamantyl). The dependence of the surface tension with concentration shows the typical profile of surfactants since a breaking point, which corresponds to the critical aggregation concentration ( cac ), is observed in all cases. The cac of these diarmed derivatives are about 1–3 orders of magnitude lower than those of classical monoalkyl derivatives used as reference compounds. In contrast to conventional surfactants, reversed trends in cac values and molecular areas at the solution–air interface have been observed. This anomalous behavior is tied to the structure of the surfactants and suggests that long and flexible alkyl chains should self-coil previous to the aggregation or adsorption phenomena. Above cac all compounds form large aggregates, globular in shape, which tend to associate forming giant aggregates.

Supramolecular rearrangements are crucial in determining the response of stimuli sensitive soft matter systems such as those formed by mixtures of oppositely charged amphiphiles. Here mixtures of this kind were prepared by mixing the cationic block copolymer pAMPTMA(30)-b-pNIPAAM(120) and an anionic surfactant obtained by the modification of the bile salt sodium cholate. As pure components, the two compounds presented a thermoresponsive self-assembly at around 30-35 degrees C; a micelle formation in the case of the copolymer and a transition from fibers to tubes in the case of the bile salt derivative. When both were present in the same solution they associated into mixed aggregates that showed complex thermoresponsive features. At room temperature, the core of the aggregate was comprised of a supramolecular twisted ribbon of the bile salt derivative. The block copolymers were anchored on the surface of this ribbon through electrostatic interactions between their charged blocks and the oppositely charged heads of the bile salt molecules. The whole structure was stabilized by a corona of the uncharged blocks that protruded into the surrounding solvent. By increasing the temperature to 30-34 degrees C the mixed aggregates transformed into rods with smooth edges that associated into bundles and clusters, which in turn induced clouding of the solution. Circular dichroism allowed us to follow progressive rearrangements of the supramolecular organization within the complex, occurring in the range of temperature of 20-70 degrees C.

The crystal structure of three head-to-head dimers (having two cholic acid or deoxycholic acid units) linked at carbon atoms C3 by aromatic or alkyl bridges is studied. An internal coordinates system is necessary for describing the relative orientation in the space of the two bile acid residues. Five angles (three torsion and two common ones) are necessary for defining the relative position of both steroid residues in space. Carbon atoms C3 (which always carries a α-hydroxy group in natural bile acids), and C10 and C13 (which always carry β-methyl groups) of each steroid residue are suitable for this purpose. Furthermore, the distance between each C3 carbon atoms of both steroid residues will allow one to locate the steroids in space. The three dimers selected provide a large range of values for these angles. The packing, hydrogen bond network, and location of guest in the three crystals are discussed.

Starting from the structure of ice (in which each water molecule is surrounded by other four water molecules forming a tetrahedron with a value of 4.51 A for the edge O-O distance), and the knowledge that this value also corresponds to the O7-O12 distance of the skeleton of cholic acid, it is hypothesized that two steroid cholic acid moieties, with an appropriate steroid-steroid distance and a belly-to-belly orientation, could encapsulate a single water molecule between them. To check this hypothesis two succinyl derivatives of cholic acid (a monomer and the related head-head dimer in which the succinyl group is the linking bridge) were designed. The expected "ice-like" structure is found in the crystal of the dimer. There is a hydrogen bond synergy between those participating in the "ice-like" structure, and those in which the bridge is involved with the O7-H hydroxy group and the side chain of the steroid. © 2012 Elsevier Inc. All rights reserved.

A structural characterization of host-guest supramolecular copolymers, formed by an adamantane dimer and two beta-cyclodextrin trimers in aqueous solution, has been carried out by combining small angle X-ray scattering and light scattering experiments. A shape-reconstruction method was applied to the SAXS data to obtain relatively high-resolution conformation information, and a correlation with the experimental dynamic light scattering results was performed, by estimating the hydrodynamic radii of the reconstructed shape through a shell model method. When applied on the solutions of the trimers, the analysis provides a globular reconstructed shape with a hydrodynamic radius in agreement with the experimental one. For the polymers, elongated structures were inferred which grow both in length and in cross section by increasing the concentration. Depending on the beta-cyclodextrin trimer employed in the polymer preparation, polymerization degrees ranging between roughly 7 and 14 or 9 and 22 were obtained in the concentration range 4.00-10.0 or 3.10-6.60 mM of the trimer (6.00-15.0 or 4.65-9.90 mM of the dimer). Aggregation schemes were proposed accounting for the formation of hyperbranched, linear, and network like polymers. The experimental results are not far from those expected on the basis of the aggregation in hyperbranched structure, for which the growth of elongated aggregates can be predicted in the early stages of the polymerization. However, the coexistence of the other structures, in particular of the linear one, cannot be ruled out.

A new gemini steroid surfactant derived from 3 alpha,12 alpha-dihydroxy-5 beta-cholan-24-amine (steroid residue) and ethylenediamintetraacetic acid (spacer) was synthesized and characterized in aqueous solution by surface tension, fluorescence intensity of pyrene, and light scattering (static and dynamic) measurements. These techniques evidence the existence of a threshold concentration (cac), below which a three layers film is formed at the air-water interface. Above the cac, two types of aggregates(-)micelles and vesicle-like aggregates(-)coexist in a metastable state. Filtration of a solution with a starting concentration of 2.6 mM (buffer 150 mM, pH 10) allows isolation of the micelles, which have an average aggregation number of 12, their density being 0.28 g cm(-3). Under conditions where only the vesicle-like aggregates are detected by dynamic light scattering, a value of 5.5 x 10(4) was obtained for their aggregation number at 30 mu M, their density being 6.8 x 10(-4) g cm(-3). At high concentrations, the intensity ratio of the vibronic peaks of pyrene, I-1/I-3, (= 0.68) is very close to published values for deoxycholate micelles, indicating that the probe is located in a region with a very low polarity and far from water. A hypothesis to explain the observed aggregation behavior (small aggregates are favored with increasing gemini concentration) is outlined.

The formation of supramolecular structures initiated by a p-tert-butyl-phenyl-amide derivative of cholic acid is investigated. The initial spherical vesicles, with a rather low effective bending constant, collapse into necklaces that self-transform into tubules of small diameter. Finally, molecular tubes are generated (see figure). During the process, the geometrical constraints of fixed surface area and fixed enclosed volume are obeyed.

Steroidal surfactants like bile salts have a rigid amphiphilic structure significantly different from the typical head–tail one. As a result, these molecules show peculiar features in their self-assembly behavior and solubilization and permeation abilities. Bile salts are widely used as starting materials in the preparation of synthetic derivatives by changing their amphiphilic structure and by introducing specific functionalities. Due to the steroid rigidity and the peculiar distribution of hydrophobic and hydrophilic domains, these molecules self-organize in ordered supramolecular assemblies and are particularly attractive for the bottom up construction of complex nanostructures. They often self-assemble in 1D structures such as tubes or fibers and show low molecular weight gelator features. Their tubular nanoscale structures have cross section diameters spanning a wide range of values (inner diameter 3–450 nm) and are sometimes formed through appealing pH or temperature responsive aggregations. Moreover, mixtures of these surfactants allow in some cases the preparation of mixed tubes with tunable composition and related features such as charge and sizes. The unconventional amphiphilic molecular structure of BSs dictates also remarkable abilities as carriers across tissues and membranes of many compounds (e.g. drugs, carbohydrates and ions). Therefore they are often employed as encapsulators, dispersants and transporters in complex systems. Chemical modifications can also be used to provide derivatives with improved performances. UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Química UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Electroquímica y Energía Química (CELEQ)

The 18th International Electronic Conference on Synthetic Organic Chemistry session General Organic Synthesis A head-to-head dimer of cholic acid linked at C3 carbon atoms by a urea bridge was synthesized and the crystal structure was studied. The crystal belongs to the monoclinic crystal system, space group I2. The packing shows a bilayer structure with alternating hydrophobic and hydrophilic layers. The horizontal and vertical planes of the two cholic residues are almost parallel to each other, the vertical ones being perpendicular to the bilayers. The hydrogen bond network is two-dimensional as it does not propagate in the direction perpendicular to the bilayers. It is noteworthy that the nitrogen atoms of the urea bridge do not participate in that network. The carbonyl urea group and only one of the ester of the two side chains form hydrogen bonds with two other dimers through the steroid hydroxy O7-H and O12-H groups. This means that each dimer forms eight hydrogen bonds but only four are different

The aggregation behavior of a cationic derivative of cholic acid {[3β,5β,7α,12α]-3-(2-naphthoylamino)-7,12-dihydroxycholan-24-triethylamonium iodide} has been studied by surface tension measurements, fluorescence spectroscopy, transmission electronic microscopy (TEM), and circular dichroism. The critical aggregation concentration, the fraction of bound counterions and thermodynamic parameters for the formation of aggregates have been determined, as well as the morphology of the aggregates. TEM images support a consecutive transformation mechanism from fibers to tubules, these having a well-defined geometry and being the only structure observed at the end of the process. Intermediate observed structures are helical ribbons.

Steady-state fluorescence and time-resolved fluorescence have been used to study sodium deoxycholate aggregates at basic pH. Pyrene was used as a probe, and dimethylaniline, as a quencher. It is concluded that dynamic quenching with partially micellized quenchers and not static quenching with the quencher totally micellized, as has been often quoted in the literature, must be considered to interpret the experimental results. Fluorescence lifetimes for pyrene in the absence of quencher and the kinetic constants involved in quenching by dimethylaniline are given and compared to those for similar systems. The derived aggregation number, equal to 8 ± 2, is close to the ones determined by other authors from freezing point depression and static light scattering. The possible distortion of these small aggregates by probes is also discussed.

The G-1 dendrimer 4,4',4'',4'''-methanetetrayltetrakis(N-(3,5-dicarboxyphenyl)benzamide) has been obtained from 4,4',4'',4'''-methanetetrayltetrabenzoic acid and isophtalic acid. The compound was recrystallized from methanol and its structure resolved. The crystal belongs to the tetragonal crystal system space group I-4 2d, the cell lengths being a=b=18.9585(16) A, and c=23.703(2) A. The crystal structure evidences the formation of cavities. Only one type of hydrogen bond is observed implying the nitrogen atom (acting as donor) and the oxygen atom of one carboxy group of the aminoisophtalic residue (as acceptor), while the other carboxy group does not participate in the network. The donor-acceptor distance is 3.024(2) A.

In this paper, the preparation and characterization of an anionic and a cationic surfactant obtained by chemical modifications of a natural bile acid (cholic acid) are reported. The bile acid was modified by introducing a diamine or a dicarboxylic aromatic residue on the lateral chain. The pure cationic surfactant self-assembles in a network of fibers with a cross-section gyration radius of about 15.1 A, providing hydrogels with a pH-dependent compactness. On the other hand, the anionic molecule gives rise to prolate ellipsoid micelles. Homogeneous catanionic mixtures have also been obtained, with molar fraction of each surfactant ranging from 0.125 to 0.875. At total surfactant concentration of 0.05% (w/v), the mixtures form gels of fibrils partially arranged in secondary twisted superstructures. Comparison of this concentration with the minimum gelation concentration of the pure cationic derivative (0.16% w/v) suggests that, in the mixtures, the presence of the electrostatic component in self-assembly of the molecules allows the formation of gels starting from more dilute samples. In view of these achievements, this work suggests that catanionic mixtures can be exploited to enhance the efficiency of gelators.

The formation of tubules by p-tert-butylphenylamide derivatives of chenodeoxycholic and ursodeoxycholic acids in aqueous solution is investigated. The critical aggregation concentrations of the new surfactants are much lower than those of ursodeoxycholate and chenodeoxycholate, indicating the enhanced surfactant properties resulting by the presence of the hydrophobic p-tert-butylphenyl group. The molecular areas at the air-water interface suggest the formation of monolayer films with molecules upright oriented. The shape of the aggregates was investigated by TEM. The main structure present in solution corresponds to tubules. The estimated value for the wall thickness of tubules suggests that a bilayer structure is formed. Host of positively charged latex beads by tubules suggests that their inner and outer surfaces are negatively charged. The acid form of the chenodeoxycholate derivative was recrystallized from toluene and its crystal structure analyzed. © 2012 Elsevier Inc. All rights reserved.

A unimer with two host binding sites of β-cyclodextrin and two guest binding sites (two p-tert-butylphenyl moities) has been synthesized. The host and guest residues are linked through an EDTA bridge. Static and dynamic light scattering measurements evidence the formation of supramolecular entities in aqueous solution with a low degree of polymerization (

Thethree-dimensionalstructureswithnanoscopicdimensionsthat are yielded by the self-assembly of lipids and surfactantsare of particular interest for their applications in nano-technology.Intheseapplications,thepossibilityofcontrollingthe charge of the particles allows the regulation of funda-mental aspects, such as the ability of the particles to loadmolecules (drugs, DNA, proteins, etc.), to aggregate, and topenetrate membranes. Within the possible surfactant supra-molecular architectures, tubular structures have recentlydrawn much research interest.

The formation of supramolecular structures initiated by a p-tert-butylphenylamide derivative of deoxycholic acid (Na-t-butPhDC) is investigated. At 1.18 mM concentration of Na-t-butPhDC and 37 degrees C, initial flat ribbons are observed which self-transform into helical ribbons (with a mean pitch angle of 47 +/- 6 degrees) which finally originate molecular tubes with an external diameter of 241 +/- 28 nm. Most of the molecular tubes show helical markings with a pitch angle value of 45 +/- 4 degrees, in full agreement with predictions of simple models based on chiral elastic properties of the membrane. A lateral association mechanism is proposed to account for the growth of the external diameter (from 225 +/- 32 to 546 +/- 59 nm) of tubes with time at 3.99 mM.

The 13th International Electronic Conference on Synthetic Organic Chemistry session Polymer and Supramolecular Chemistry

The reaction of 3beta-aminoderivatives of cholic and deoxycholic acids (steroid residues) with dimethyl ester of ethylenediaminetetraacetic acid (bridge) leads to the formation of dimers carrying four carboxylic organic functions, two of them located on the side chain of each steroid residue and the other two on the bridge. As tetrasodium salts, these new compounds behave as surfactants and have been characterized by surface tension, fluorescence intensity of pyrene (as a probe), and static and dynamic light scattering measurements. Thermodynamic parameters for micellization were obtained from the dependence of the critical micelle concentration (cmc) with temperature. For both surfactants, the fraction of bound counterions is close to 0.5. The aggregation behavior is similar to one of their bile salt residues [i.e., sodium cholate (NaC) and sodium deoxycholate (NaDC)] and can be summarized as follows: (i) molecular areas at the interface for the new surfactants are fairly close to twice the value for a single molecule in a monolayer of natural bile salts; (ii) the environment where pyrene is solubilized is very apolar, as in natural bile salt aggregates; (iii) Gibbs free energies (per steroid residue) for micellization are not far from published values for NaC and NaDC, and the differences can be understood on the basis of less hydrophobicity of the new surfactants due to the charges in the bridge; and (iv) as for NaC and NaDC, aggregates have rather low aggregation numbers (which depend on the amount of added inert salt, NaCl). A structure based on the disklike model accepted for small bile salt aggregates is proposed.

We report a kinetic study of the supramolecular tubule formation of the bile salt derivative [3β,5β,7α,12α]-3-(4-t-butylbenzoilamine)-7,12-dihydroxycholan-24-oic acid sodium salt (Na-tbutPhC). At high bicarbonate buffer concentration (pH∼10) this salt shows gelator properties. Starting from gels or viscous solutions, the tubule formation is triggered by increasing the temperature beyond the critical value of 34–36 °C. For gels, when the process takes place, the transition to sols occurs. The process is easily triggered and can be followed by several techniques. We used static light scattering (SLS), circular dichroism (CD), small angle X-ray scattering (SAXS) along with transmission electron (TEM) and optical microscopies. The CD results show that fibrils with a clockwise arrangement of the bile salt derivative are present in the samples at room temperature. When the tubule formation starts, evolutions of the CD and SLS profiles are observed indicating that the formation process begins with the aggregation of the fibrils accompanied by a simultaneous peculiar reciprocal reorientation of the surfactant molecules. After that, as pointed out by the long time evolution of the curves, a slow transformation towards the final well defined tubules occurs, involving an adjustment of the molecular packing. In the meanwhile, the slow ordering of the tubule walls in well spaced layers takes place, as inferred by SAXS. The TEM images show that short disordered tubules are formed, because of the aggregation of fibrils, in the beginning. Moreover they highlight a final elongation of the tubules taking place without a further aggregation of fibrils. Optical microscopy frames, collected during the process, point out that the tubules grow singly even at quite a high concentration, thus supporting the data interpretation.

The 13th International Electronic Conference on Synthetic Organic Chemistry session Polymer and Supramolecular Chemistry The binding constants, standard molar enthalpy, Gibbs free energy, and entropy changes were determined for the formation of complexes between adamantyl derivatives and a β-cyclodextrin dimer. It is concluded that, within experimental error, the two cyclodextrin residues in the dimer behave independent to each other when complexing the adamantyl derivatives The authors from USC thank the Ministerio de Ciencia y Tecnología (Project MAT2004-04606) and Xunta de Galicia (PGIDIT05PXIC26201PN) for financial support

The 13th International Electronic Conference on Synthetic Organic Chemistry session Polymer and Supramolecular Chemistry The binding constants, standard molar enthalpy, Gibbs free energy, and entropy changes were determined for the formation of inclusion complexes between 3α,7α,12α- trihydroxy-5β-cholan-24-amine, C24NH2, and β-cyclodextrin and γ-cyclodextrin. The stoichiometry of both complexes is 1:1 in agreement with previously reported results for other trihydroxy bile salts. The equilibrium constant values for the formation of the inclusion complex are similar as well. The structure of the C24NH2/γ-cyclodextrin complex was studied by ROESY experiments. These results suggest that B, C and Drings of the steroid skeleton, as well as the side chain, interact with the cyclodextrin cavity, while the A ring of the steroid nucleus remains outside the cavity The authors from USC thank the Ministerio de Ciencia y Tecnología (Project MAT2004-04606) and Xunta de Galicia (PGIDIT05PXIC26201PN) for financial support

The 12th International Electronic Conference on Synthetic Organic Chemistry session Supramolecular Chemistry A new gemini steroid surfactant derived from 3a,7a,12a-trihydroxy-5ß-cholan-24-amine (steroid residue) and ethylenediamintetraacetic acid (spacer) was synthesized and characterized in aqueous solution by surface tension measurements and fluorescence intensity of pyrene. These techniques evidence the existence of a threshold concentration, cac, below which a three layers film is formed at the air-water interface. At high concentrations, the intensity ratio of the vibronic peaks of pyrene, I1/I3, (= 0.81) is very close to published values for sodium cholate micelles, indicating that the probe is located in a region with a very low polarity and far from water The authors from USC thank the Ministerio de Ciencia y Tecnología (Project MAT2004-04606) and Xunta de Galicia (PGIDIT05PXIC26201PN) for financial support

A detailed characterization of a host-guest supramolecular copolymer, formed by adamantane and beta-cyclodextrin dimers (Ad(2) and beta CD2, respectively) in aqueous solution, has been carried out by combining small-angle X-ray scattering and light scattering experiments with molecular dynamics (MD) and Monte Carlo (MC) simulations. First, the solutions of the monomers were studied by a straightforward analysis of the scattering data. Afterward, the complex given by Ad(2) and two beta-cyclodextrin molecules was investigated by correlating scattering results and MD simulations, to characterize the host-guest linkage. Finally, a detailed interpretation of the polymer scattering data was achieved by MC simulations. These simulations were performed on a single supramolecular aggregate and, in view of its peculiar shape, the complete polymer structure was considered without resorting to more general but simplified chain models. The comparison between simulations with and without excluded volume interaction points out that, at our ionic strength (sodium azide 150 mM), the polymer is close to the theta condition. Fits by reverse MC methods show that the polymer presents a shrunk conformation in solution, but it does not close in stable cyclic structures, as generally hypothesized for this kind of small oligomer. However, a polymerization degree of about 8 (4 Ad(2) and 4 beta CD2) was estimated which does not show any concentration dependence.

Since the beta-cyclodextrin cavity is not a smooth cone but has constrictions in the neighborhoods of the H3 and H5 atoms, the hypothesis that bulky hydrophobic guests can form two isomeric inclusion complexes (one of them, c(p), is formed by the entrance of the guest by the primary side of the cavity, and the other one, c(s), results from the entrance by the secondary side) is checked. Thus, the inclusion processes of two 1-substituted adamantyl derivatives (rimantidine and adamantylmethanol) with beta-cyclodextrin and its two monoamino derivatives at positions 6 (6-NH2beta-CD) and 3 (3-NH2beta-CD) were studied. From rotating-frame Overhauser enhancement spectroscopy experiments, it was deduced that both guests form c(s) complexes with beta-CD and 6-NH2beta-CD but c(p) complexes with 3-NH2beta-CD. In all cases, the hydrophilic group attached to the adamantyl residue protrudes toward the bulk solvent outside the cyclodextrin cavity. The thermodynamic parameters (free energy, equilibrium constant, enthalpy, and entropy) associated with the inclusion phenomena were measured by isothermal titration calorimetry experiments. From these results, the difference in the free energy for the formation of the two complexes, c(s) and c(p), for the same host/guest system has been estimated as being 11.5 +/- 0.8 kJ mol(-1). This large difference explains why under normal experimental conditions only one of the two complexes (c(s)) is detected. It is also concluded that a hyperboloid of revolution can be a better schematic picture to represent the actual geometry of the cyclodextrin cavities than the usual smooth cone or trapezium.

The self-aggregation of the sodium salt of a new adamantyl amide of the 3beta-amino derivative of cholic acid (Na-AdC) in aqueous solution has been investigated by surface tension, dynamic light scattering, fluorescence, small-angle X-ray scattering (SAXS), and transmission electron microscopy (TEM) measurements. These last two techniques suggest that a lamellar phase, consisting of charged bilayers of Na-AdC separated by solvent and periodically stacked, is formed in aqueous solution. The structure of the bilayer is inferred from the resolution of the crystal of the compound in its acid form. The adamantyl moieties, which are mutually interlocked, reside in the central region of the bilayer, and the carboxylic groups are directed toward the hydrophilic region. The structure is open enough to allow water molecules to interact with a fluorescence probe located at the central hydrophobic region.

An amino derivative of beta-cyclodextrin [6-(6-aminehexanamide)-6-deoxy)-beta-cyclodextrin (6-betaCD)] was synthesized, and the formation of an intramolecular inclusion complex was studied by NMR techniques. The deprotonation/protonation of the amino group stimulates an in/out movement of the pendant group toward/from the cyclodextrin cavity, the protonated species lying outside the hydrophobic cyclodextrin cavity but the unprotonated one residing inside and outside the cavity. The protonation of the amino group is a fast exchange rate NMR time-scale process, but the chain movement is a slow one. The equilibrium constants of both processes were determined from 1H NMR experiments and the kinetic constants for the slow process were determined from exchange spectroscopy (EXSY) experiments.

The interactions between three beta-cyclodextrin hosts (having 1-3 binding sites) and two adamantyl guests (having 1-2 binding sites) have been studied by ITC, ROESY, static and dynamic light scattering (SLS and DLS), and AFM and TEM techniques. The enthalpy and free energy values (determined from ITC experiments) evidence that the single interaction between one binding site of the guest and one binding site of the host is independent of the number of binding sites of the interacting species. The average values are deltaH degrees = -26.6 +/- 2.3 kJ mol(-1) and deltaG degrees = -30.4 +/- 3.2 kJ mol(-1), indicating that the process is mainly enthalpy driven. In all cases, the experimental molar ratio (from ITC experiments) agrees with the expected one from the number of binding sites of both the host and guest. The formation of polymer-like entities was demonstrated by SLS, DLS, AFM, and TEM measurements. The structure of polymers is linear when both the host and the guest are ditopic entities and dendritic (or Cayley tree type) when the host and the guest have three and two binding sites, respectively.

The 10th International Electronic Conference on Synthetic Organic Chemistry session Supramolecular Chemistry The self-aggregation in aqueous solution of a new neo-pentyl amide of the 3-β-amino derivative of cholic acid (Na-n-penC) has been investigated in aqueous solution by surface tension and steady state-fluorescence spectroscopy of pyrene (used as a probe). The nature of the agregates was determined by transmission electron microscopy (TEM) revealing that vesicles are formed. The structure of the compound in the solid state was resolved by X-ray spectroscopy. The synthesis of the compound is also given

Mono-6-deoxy-6-adamantylamide-β-cyclodextrin–dimethylformamide–15H2O, C53H85NO35·C3H7NO·15H2O, crystallizes in the orthorhombic space group P212121. The adamantyl group is inserted into the cyclodextrin cavity of the adjacent molecule, entering by the side of the secondary hydroxy rim, thus forming a supramolecular linear polymer by self-assembly. Adjacent macrocycles are linked into columns by hydrogen bonds involving the nearest glucose residues, and the structure is further stabilized by their involvement in hydrogen bonding with water molecules which reside in channels surrounding the polymer columns, thus acting as bridges between the cyclodextrin units. The centroid of the adamantyl group lies below the plane formed by the seven glycosidic O atoms of the host cyclodextrin, excluding water molecules from the secondary side of β-cyclodextrin (β-CD). Between the adamantyl group and the primary hydroxy rim of the cyclodextrin cavity lies a dimethylformamide molecule, which shields the hydrophobic adamantyl group from the primary hydroxy rim of its carrying β-CD and excludes water molecules from the primary side of the β-CD cavity.

New double-chain surfactants can be designed in which nitrilotriacetic acid plays the role of glycerol in phospholipids. The synthetic methodology is applied to the synthesis of (2-(bis(2-dodecylamino)-2-oxoethyl)amino)acetic acid. This is a symmetric dimeric surfactant but the methodology allows the synthesis of asymmetric double-chain surfactants as well. The Krafft temperature is 16–18 °C. The critical aggregation concentration of the new surfactant (4.76 × 10−5 mol dm−3 in NaOH 0.01 M and 25 °C; surface tension measurements) is two hundred times lower than that for sodium 2-dodecanamidoacetate, which can be considered its monoalkyl surfactant analog, indicating the enhanced surfactant properties resulting from the presence of two hydrophobic alkyl chains. The shape of the aggregates was investigated by transmission electron microscopy. At 40 °C, the main structure present in solution corresponds to vesicles and, from the size distribution of their radii, values of (0.34 ± 0.06)kT and 56.7 ± 2.6 nm were obtained for the effective bending elasticity constant and the spontaneous radius of curvature of vesicles, respectively.

Tubules formed by self-assembly of organic molecules have vast potential for nanotechnology applications, and the introduction of sensitivity to stimuli into self-assembly tubules represents a particularly attractive feature. Here we report the preparation and characterization of a molecule obtained by chemical modification of a natural bile acid, a biological surfactant, that self-assembles in pH sensitive tubules in aqueous solutions. The tubules, which are rigid, single-walled and with a diameter of 60 nm, form at pH 8-9 and open up when the pH is increased. The transition is reversible, it occurs in the pH range of 9-10 with an opening mechanism that is remarkably different from those so far proposed in the literature. It involves a release of wall layers similar to leaves, and is determined by a drastic pH-triggered change in the molecular arrangement, which in turn induces a radical modification of the wall curvature. The description of the morphological transformation is provided by means of cryogenic transmission electron microscopy and represents, to our knowledge, the first detailed visualization of pH stimulated tubule opening. UV and circular dichroism spectroscopies are used to investigate the evolution at the molecular level.