甘脲类分子胶囊受体合成方法的研究进展

甘脲类分子胶囊是一类独特的由非共价键弱相互作用力组装而成的人工受体, 在分子识别、自组装、分子微反应器、智能材料等方面得到了广泛而深入的研究. 系统综述了网球型(Tennis ball)、垒球型(Softball)、足球型(Football)及圆盘型(Jelly Doughnut)等分子胶囊的合成方法.     

A New Anion Receptor with a Glycoluril Molecular Scaffold

The rational design and synthesis of a new anion receptor containing a glycoluril molecular scaffold are reported. This new receptor utilizes four amide hydrogen bonds arranged at the corner of the glycoluril unit. This new anion receptor binds spherically shaped halide ions in a 1:1 stoichiometry and has a high affinity for fluoride.     

Cucurbit[n]uril formation proceeds by step-growth cyclo-oligomerization

In contrast to the high yield formation of cucurbit[n]uril (CB[n]) from a 1:2 ratio of glycoluril to formaldehyde, the condensation of glycoluril with less than 2 equiv of formaldehyde delivers a reaction mixture that contains glycoluril oligomers (2-6) and CB[n] compounds that lack one or more methylene bridges known as nor-seco-cucurbit[n]urils (ns-CB[n]). In this paper we report the chromatographic purification of C-shaped glycoluril oligomers (dimer-hexamer), their characterization in solution, and their X-ray crystal structures. Quite interestingly, despite being acyclic glycoluril pentamer 5 and hexamer 6 retain the ability to bind to guests typical of CB[6] but are also able to expand their cavity to accommodate larger guests like cationic adamantane derivatives. We performed product resubmission experiments with glycoluril oligomers 2-6 and found preferences for the formation of specific ring sizes during CB[n] formation. A comprehensive mechanistic scheme is proposed that accounts for the observed formation of 2-6 and ns-CB[n]. Overall, the experiments establish that a step-growth cyclo-oligomerization process operates during CB[n] formation.     

Chiral softballs: synthesis and molecular recognition properties.

Studies on the different congeners of the softball were undertaken to explore structural variants for enantioselective encapsulation. Two different spacer elements in the monomeric subunit render the dimeric softball chiral although the monomer itself is achiral. The dimers represent capsules with dissymmetric cavities with volumes ranging from 190 to 390 A(3). The cavities are distorted spheres, and asymmetric guests, such as naturally occurring terpenes, generally prefer one enantiomer of the capsule to its mirror image. The selectivities are moderate (up to 4:1). The complexation studies show that the host capsules are flexible enough to arrange themselves comfortably around a guest but still maintain enough rigidity to be influenced by the occupancy of a chiral guest. The enantiomeric capsules can interconvert (racemize) by dissociation and recombination of their subunits.     

Self-assembled (pseudo)rotaxane and polyrotaxane through host–guest chemistry based on the cucurbituril family

Cucurbit[n]uril and its derivatives, a new family of macrocyclic hosts comprising n glycoluril units, have gained much attention for their exceptional application in many fields. In this review, we introduced the cucurbituril family and the development of its derivatives, which can be used in the molecular recognition and self-assembled materials such as pseudorotaxane, polyrotaxane. Moreover, cucurbituril provides the possibility to design stimulus–response devices and imitate the life secret at molecule level, such as the molecular devices controlled by pH, photochemistry, thermal and so on.     

Synthesis, computational study and binding properties of some structurally rigid glycoluril-derived molecular clips

Several new clip-shaped molecules, with different degrees of steric hindrance around their cavities as well as more rigidity on their glycoluril scaffold, have been synthesized and the molecular geometry of their most stable structures has been investigated and optimized with density functional theory (DFT) at the B3LYP level of theory using 6-311G basis set. The affinity of these molecular clips for some dihydroxybenzene derivatives (guests) has been computationally and experimentally studied. The clips having dimethyl-substituted aromatic side walls, showed the best interaction energies towards the mentioned guests. Also, the computational results revealed that the more electron-deficient guest interacts more strongly with the clips (hosts).     

Synthesis of a symmetrical octamethyl-substituted cucurbituril with a dimethyl-substituted glycoluril dimer

A symmetrical octamethyl-substituted cucurbituril has been synthesized in a controlled manner by using a dimer of dimethyl-substituted glycoluril, which was in turn synthesized under formaldehyde-deficient conditions. The dimer of dimethyl-substituted glycoluril and the symmetrical octamethyl-substituted cucurbituril have been characterized by NMR spectrometry, ESI mass spectrometry and single-crystal X-ray diffraction analysis. The structure of the dimer of dimethyl-substituted glycoluril is notable because it constitutes a useful new building block that could permit the formation of such cucurbit[n]urils with substituents in certain positions or with limited numbers of methine groups on their backbones.     

Synthesis and computational study of two new glycoluril clips containing benzocrown ether side walls

Two new glycoluril-derived molecular clips containing benzocrown ether side walls have been synthesized via reaction of a glycoluril scaffold with two bromomethylated benzocrown ethers. The molecular geometry of their most stable structures were investigated with density functional theory at the B3LYP level of theory using STO-3G, 6-31G, and 6-311G basis sets. Then based on the obtained computer-optimized structures, the binding properties of one clip with some 5-substituted resorcinols have been calculated.     

Self-Assembling Sieves

A modular strategy has been applied to synthesize large, porous, self-assembling capsules. The coupling of tricyclic building blocks incorporating glycoluril hydrogen-bonding units and derivatives of triethylbenzene produces monomers which readily form homo- and heterodimeric assemblies (calculated structure is shown). Large guests can be trapped while small solvent molecules flow freely through the pores of the capsules.     

Functionalized cucurbiturils and their applications

Cucurbit[n]uril (CB[n], n = 5-10), a new family of molecular hosts comprising n glycoluril units, have gained much attention in the new millennium for their exceptional molecular recognition ability. The CB homologues have brought dynamism to CB chemistry, as witnessed by the heightened interest in the field for the last several years. Compared to the chemistry of cyclodextrins and calixarenes, however, that of CB[n] has developed slowly until recently, which may be attributed mainly to their poor solubility in common solvents, and inability to functionalize these molecules. The direct functionalization method of CB[n] propelled CB chemistry to a new height as this new method not only solved the solubility problem but also opened up the gateway to the generation of tailor-made CB[n] derivatives. The functionalization of CB[n] led us to investigate numerous applications including artificial ion channels, vesicles, stationary phases in chromatography, ISEs, polymers, nanomaterials, and many others. This tutorial review describes the recent advances and challenges in the functionalization of CBs along with the applications of functionalized CBs.     

Theoretical investigation on electronic structure and stability of some inverted cucurbiturils by density functional theory

Structure and stability of diastereoisomers of cucurbit[n]urils (CB[n = 5–10]), the inverted CB[n]s, were investigated by density functional theory (DFT) computations. All the inverted CB[n]s were less stable than their normal CB[n]s and the mono-inverted ones with one inverted glycoluril unit in their structures were more stable than their doubly-inverted isomers. Relative change in dipole moments and molecular electrostatic potentials (MEP) were discussed with the deformation in geometric structure and charge distribution of the normal and inverted CB[n]s.     

Polymer microcapsules with "foamed" membranes

This article describes the preparation of capsules displaying craters at their surfaces and independent holes inside their membranes. These poly(methylmethacrylate) capsules of 20 to 200 microm diameter are prepared by a solvent evaporation process and typically contain a dispersant, polyvinyl alcohol, and an excipient, namely, a fatty acid triglyceride (miglyol 812). Spectroscopic methods showed that, depending on the miglyol content, the craters at the surface exhibited sizes of about 1 to 2 microm, whereas the core structure of the membrane changed significantly, typically from "soft-part-of-bread" up to "foamed"-like aspects. Among several spectroscopy techniques, confocal fluorescence microscopy confirmed that the capsules retained the miglyol in their core and not in the craters or holes, even after centrifugation and handling. This technique also showed that holes in the membrane are filled with water. A possible analysis of the "foaming" phenomenon based on the surface tensions of different oils, as well as their optimal hydrophile-lipophile balance (HLBO), is added to generalize the concept.     

New molecular shapes for recognition and catalysis

Progress in molecular recognition is reviewed with special emphasis on the advantages offered by molecular clefts. These new structures are rapidly assembled from readily accessible starting materials and feature functional groups that converge on smaller species that present complementary surfaces. The sizes and shapes of the clefts are controlled by the use of appropriate spacer elements. The selective binding of acids, amines, amino acids, metal ions, heterocyclic compounds and nucleosides is described. Their special applicability to problems involving concerted catalysis is also introduced.     

Molecular shuttles by the protecting group approach

Two new [2]rotaxane-based molecular shuttles, in which a mechanically bound dibenzo[24]crown-8 (DB24C8) macroring shunts back and forth between two dialkylammonium recognition sites situated on a chemical dumbbell, have been constructed by a novel synthetic strategy that relies upon the use of the tert-butoxycarbonyl (Boc) protecting group. During the syntheses of both molecular shuttles, this protecting group masks a dialkylammonium recognition center which is liberated only after the [2]rotaxane constitution is established. In both cases, the molecular shuttles' other dialkylammonium center is essential for the rotaxane-forming reactions and it ensures that DB24C8 is interpenetrated by threadlike precursors, as a result of noncovalent bonding interactions, to produce [2]pseudorotaxanes which are stoppered subsequently through 1,3-dipolar cycloadditions between azides and bulky acetylenedicarboxylates. The new molecular shuttles have been examined by means of dynamic 1H NMR spectroscopy, which reveals that the movements of the DB24C8 macroring are very highly dependent both on solvent properties and on the nature of the spacer unit linking the two dialkylammonium centers. Thus, DB24C8 shunts facilely between the dialkylammonium centers when the shuttles are dissolved in solvents that readily donate their nonbonding electrons into noncovalent bonds, e.g., DMF, and when spacer units that do not offer much steric resistance to shuttling, e.g., hexamethylene, are used. On the other hand, shuttling is difficult in solvents that are less inclined to donate their electrons into noncovalent bonds, e.g., (CDCl2)2, and when relatively bulky benzenoid spacer units, e.g., p-xylylene, link the two dialkylammonium centers. It has been proposed that the DB24C8 might act as a "ferry" which carries a proton between dialkylammonium and dialkylamine moieties in a singly protonated [2]rotaxane by means of ion-dipole interactions.     

Methylene-bridged glycoluril dimers: synthetic methods

Methylene-bridged glycoluril dimers are the fundamental building blocks of cucurbituril (CB[6]), its homologues (CB[n]), and its derivatives. This paper describes three complementary methods for the synthesis of C- and S-shaped methylene-bridged glycoluril dimers (29-34 and 37-44). For this purpose, we prepared glycoluril derivatives (1a-d) bearing diverse functionalities on their convex face. These glycoluril derivatives were alkylated under basic conditions (DMSO, t-BuOK) with 1,2-bis(halomethyl)aromatics 6-15 to yield 4a-d and 16-24, which contain a single aromatic o-xylylene ring and potentially nucleophilic ureidyl NH groups. Glycoluril derivatives bearing potentially electrophilic cyclic ether groups (5a-f) and 25-28 were prepared by various methods including condensation reactions in refluxing TFA containing paraformaldehyde. The condensation reactions of 4a-d and 16-24 with paraformaldehyde under anhydrous acidic conditions (PTSA, ClCH(2)CH(2)Cl, reflux) give, in most cases, the C-shaped and S-shaped methylene-bridged glycoluril in good to excellent yields. In many cases, the C-shaped compound is formed preferentially with high diastereoselectivity. Cyclic ethers 5a,d-f and 25-26 undergo highly diastereoselective dimerization reactions to yield methylene-bridged glycoluril dimers with the formal extrusion of formaldehyde. Last, it is possible to perform selective heterodimerization reactions using both cyclic ethers and glycoluril derivatives bearing ureidyl NH groups. These reactions deliver the desired C- and S-shaped heterodimers with low to moderate diastereoselectivities. This heterodimerization route is the method of choice in cases where the homodimerization reactions fail. The formation of side products (+/-)-35b and (+/-)-35d helps clarify the electronic requirements for a successful CB[n] synthesis. The X-ray structures of 30C, 38C, and 38S allow for a discussion of the structural features of this class of compounds.     

Simple and direct determination of active ingredients in drugs by neutron activation analysis

The increasing number of drugs in the market and the need for their control requires new, simple, fast and accurate methods of analysis. The elements iodine, iron, manganese, silver and sodium were determined by Instrumental Neutron Activation Analysis in various pharmaceutical formulations, representing capsules, injectables, powders for injection, solutions and tablets. From the results it appears that Neutron Activation Analysis could be used as an official method for the determination of the elements iron, manganese and silver in pharmaceutical products, in which these elements are present as active ingredients, as well as for the control of the concentration limits for iodine and sodium.     

A novel dansyl-appended glycoluril-based fluorescence sensor for silver ions

Tetra-dansylated diphenyl glycoluril has been synthesized and evaluated for ionic recognition. The synthesized molecular receptor shows selective response to silver ions as determined through the enhancement of fluorescence intensity.     

A water soluble tetramethyl-substituted cucurbit[8]uril obtained from larger intermediates?

A new water soluble tetramethyl-substituted cucurbit[8]uril (Me₄Q[8]) was easily isolated from cucurbit[n]uril product mixture which was synthesized by using the dimer of glycoluril and diether of dimethyl substituted glycoluril. Crystal structure analysis shows that Me₄Q[8] is constructed of building blocks: three dimmers and two dimethyl glycolurils, the two dimethyl glycolurils are separated by a dimer of glycoluril. It is speculated that Me₄Q[8] is degraded by a larger hexamethyl substituted Q[9] or larger intermediates.     

Ligand-template directed assembly: an efficient approach for the supramolecular encapsulation of transition-metal catalysts

Supramolecular encapsulation of small guest molecules inside well-defined cavities of molecular capsules has witnessed broad attention because of the unusual behaviour of these systems. The molecular capsules generally consist of rigid complementary building blocks that are held together by multiple, complementary non-covalent interactions. Interestingly, it has been shown that chemical transformations can take place inside these capsules and in some examples the reaction is accelerated, while in other cases otherwise instable intermediates could be isolated in the capsulated form. Many reactions of interest require a transition-metal (TM) catalyst, and the creation of new capsules in which such catalysts are implemented within the structure is thus required for the development of resourceful type of catalyst systems for these processes. In this concept article we will discuss new strategies to arrive at such systems, with a focus on a ligand-templated approach. In this approach, multifunctional ligands are used as templates for the encapsulation process by supramolecular building blocks and concomitantly for the formation of TM complexes that are active in catalytic processes. The obtained encapsulated transition-metal catalysts show unusual reactivity and selectivity behaviour that will be discussed in detail.     

The inverted cucurbit[n]uril family

We report the isolation, characterization, and recognition behavior of iCB[6] and iCB[7], which are diastereomers of CB[6] and CB[7], respectively, containing a single inverted glycoluril unit. Product resubmission experiments establish that these inverted CB[n] are intermediates in the mechanism of CB[n] formation. As a consequence of the inverted glycoluril ring, these inverted cucurbiturils possess a permanent dipole moment, are slightly smaller than their diastereomers, show distinctive selectivity in their recognition behavior, and report directly on the contents of their hydrophobic cavity.