A novel synthesis of 2'-hydroxy-1',3'-xylyl crown ethers

Six novel 2' - hydroxy - 1',3' - xylyl crown ethers (8a–e and 13)1 have been synthesized utilizing the allyl group to protect the OH function during the cyclization reaction. The macrocycles 6a-e were formed in yields of 26 to 52%, by intermolecular reaction of 4 - chloro - 2,6 - bis(bromomethyl) - 1 - (2 - propenyloxy)benzene (5) with polyethylene glycols; 6a was also obtained by an intramolecular cyclization reaction of monotosylate 14.\ud A 30-membered ring with a 2' - hydroxy - 1',3' - xylyl sub-unit was obtained in 87% yield by reaction of ditosylate 9 with bis [2 - (o - hydroxyphenoxy)ethyl]ether (11) in the presence of cesium fluoride. The synthesis of crown ethers with a 2' - hydroxy - 1',3' - xylyl sub-unit (1c–e, H for CH3) by demethylation of the corresponding 2'-methoxy crown ethers 1c–e with lithium iodide were unsuccessful; it would appear that the demethylation reaction is restricted to 15- and 18-membered rings. One of the 2' - hydroxy - 1',3' - xylyl crown ethers 8d forms a crystalline 1:1-complex with water

Effect of base–acid properties of the mixtures of water with methanol on the solution enthalpy of selected cyclic ethers in this mixture at 298.15 K

The enthalpies of solution of cyclic ethers: 1,4- dioxane, 12-crown-4 and 18-crown-6 in the mixture of water and methanol have been measured within the whole mole fraction range at T = 298.15 K. Based on the obtained data, the effect of base–acid properties of water– methanol mixtures on the solution enthalpy of cyclic ethers in these mixtures has been analyzed. The solution enthalpy of cyclic ethers depends on acid properties of water– methanol mixtures in the range of high and medium water contents in the mixture. Based on the analysis performed, it can be assumed that in the mixtures of high methanol contents, cyclic ethe

Catalysis by alkali and alkaline-earth metal ions in nucleophilic attack of methoxide ion on crown ethers bearing an intra-annular acetoxy group

Rates of reaction of methoxide ion with crown ethers bearing an intra-annular acetoxy group are markedly enhanced by alkali and alkaline-earth metal bromides as a result of much stronger interactions of the metal ions with transition states than with reactants.\ud \ud Rates of reactions of methoxide ion with crown ethers bearing an intra-annular acetoxy group markedly enhanced by alkali and alkaline-earth metal bromides as a result of much stronger interactions of the metal ion with transition state than with reactants

Crown ethers: novel permeability enhancers for ocular drug delivery?

Crown ethers are cyclic molecules consisting of a ring containing several ether groups. The most common and important members of this series are 12-crown-4 (12C4), 15-crown-5 (15C5), and 18-crown-6 (18C6). These container molecules have the ability to sequester metal ions and their complexes with drugs are able to traverse cell membranes. This study investigated 12C4, 15C5 and 18C6 for their ability to increase solubility of ocular drugs and enhance their penetration into the cornea. Phase solubility analysis determined crown ethers’ ability to enhance the solubility of riboflavin, a drug used for the therapy of keratoconus, and these solutions were investigated for ocular drug permeation enhancing properties. Atomic absorption spectroscopy demonstrated crown ether solutions ability to sequester Ca2+ from corneal epithelia and crown ether mediated adsorption of riboflavin into the stroma was investigated. Induced corneal opacity studies assessed potential toxicity of crown ethers. Crown ethers enhanced riboflavin’s aqueous solubility and its penetration into in vitro bovine corneas; the smaller sized crown ethers gave greatest enhancement. They were shown to sequester Ca2+ ions from corneal epithelia, doing so loosens cellular membrane tight junctions thus enhancing riboflavin penetration. Induced corneal opacity was similar to that afforded by benzalkonium chloride and less than is produced using polyaminocarboxylic acids. However, in vivo experiments performed in rats with 12C4 did not show any statistically significant permeability enhancement compared to enhancer-free formulation

Synthesis of Novel Bibrachial Lariat Ethers (BiBLEs) Containing [1,2,4]Triazolo[3,4-b][1,3,4]Thiadiazines

A practical and regioselective method for the synthesis of cis-diastereomers of bibrachial lariat ethers (BiBLEs) bearing ester and amide groups is reported. The novel bibrachial lariat ethers (BiBLEs) 3a–d with neutral side chains were prepared by reaction of the corresponding aza-crown macrocycles 1a–b with ethyl chloroacetate and chloroacetamide.KEYWORDS macrocycle, bibrachial, lariat ethers, aza-crown, 1,3,4-thiadiazines

Amplification of the index of refraction of aqueous immersion fluids with crown ethers

There is a current need for high refractive index (RI) materials that can be used in aqueous systems for improving 193-nm immersion photolithography. Although heavy metal salts such as Ca2+ and Ba2+ have the potential to substantially increase the RI of aqueous solutions, the water solubility of these salts with common anions is often too low to achieve concentrations that significantly increase the RI to the desired values. We therefore investigate the use of crown ethers to enhance the solubility of these cations. Most of crown ethers are soluble in water, are inexpensive materials, and are available commercially. 15-crown-5-ether and 12-crown-4-ether are liquids at room temperature and therefore can be used as neat immersion fluids without dilution in water. Saturation of crown ethers with inorganic salts do not lead to any increase in the refractive index due to their low solubility in such an apolar medium. Thus, the use of inorganic salts as refractive index enhancement agents does not seem to be a desirable proposition in the present case. Instead, the use of crown ethers or their derivatives can be an alternative system, since these compounds have properties such as density, viscosity, and boiling point similar to aqueous media

Computerized conductometric determination of stability constants of complexes of crown ethers with alkali metal salts and with neutral molecules in polar solvents

A computerized conductometric procedure for the determination of stability constants of the complexes of crown ethers (15-crown-5, benzo-15-crown-5 and 12-crown-4) with alkali metal salts in polar solvents is described, based on a microcomputer-controlled titration system. For the control of the experiments from software, a modular computer program was written in FORTH computer language. The procedure is especially suitable for the study of 1:2 metal ion/ligand complexes, which occur frequently with the compounds used. For the study of the interaction between crown ethers and neutral molecules, an indirect procedure is outlined

Direct synthetic routes to functionalised crown ethers

open5noAcknowledgements Financial support from the European Union’s H2020 Research and Innovation Program (FET-OPEN “MAGNIFY”No. 801378 and ERC AdG “LEAPs”No. 692981) is gratefully acknowledged.Crown ethers are macrocyclic hosts that can complex a wide range of inorganic and organic cations as well as neutral guest species. Their widespread utilization in several areas of fundamental and applied chemistry strongly relies on strategies for their functionalisation, in order to obtain compounds that could carry out multiple functions and could be incorporated in sophisticated systems. Although functionalised crown ethers are normally synthesised by templated macrocyclisation using appropriately substituted starting materials, the direct addition of functional groups onto a pre-formed macrocyclic framework is a valuable yet underexplored alternative. Here we review the methodologies for the direct functionalisation of aliphatic and aromatic crown ethers sporadically reported in the literature over a period of four decades. The general approach for the introduction of moieties on aliphatic crown ethers involves a radical mediated cross dehydrogenative coupling initiated either by photochemical or thermal/chemical activation, while aromatic crown ethers are commonly derivatised via electrophilic aromatic substitution. Direct functionalization routes can reduce synthetic effort, allow the later modification of crown ether-based architectures, and disclose new ways to exploit these versatile macrocycles in contemporary supramolecular science and technology.openNicoli, Federico; Baroncini, Massimo; Silvi, Serena; Groppi, Jessica; Credi, AlbertoNicoli, Federico; Baroncini, Massimo; Silvi, Serena; Groppi, Jessica; Credi, Albert

Synthesis and Cytotoxicity of Silicon and Germanium Containing Pyridine Oxime O-Ethers

Silicon and germanium containing pyridine aldoxime, ketoxime and amidoxime O-ethers have been prepared using phase transfer catalytic systems oxime alkyl halide solid KOH 18-crown-6 benzene and oxime alkyl halide solid K2CO3 or Cs2CO3 18-crown-6 toluene. Cytotoxic activity of silicon and germanium containing pyridine oxime O-ethers was tested in vitro on two monolayer tumor cell lines: MG- 22A (mouse hepatoma) and HT-1080 (human fibrosarcoma). O-[3-Yriethylsilylpropyl]- and O-[3-(1-methyl- 1-silacyclopentyl)propyl] oximes of pyridine aldehydes and ketones exhibit high cytotoxicity. Presence of methyl group in the pyridine ring considerably decreased activity of amidoxime O-ethers. Oxime ethers containing two elements are essentially inactive. For 2-acetylpyridine oxime ethers the activity increases in order of alkyl substituents: Et3GeCH2CH2SiMe2CH2 < Et3SiCH2CH2CH2 < (CH2)4SiCH2CH2CH2. Cytotoxicity of ketoxime O-ethers is considerably lower in comparison with aldoxime O-ethers

Solid-liquid (S-L) an liquid (L-L) phase transfer of salts via ‘encapsulated’ crown ether cation complexes

In recent years crown ethers have been successfully used for the transport of salts, both inorganic and organic, from an aqueous phase to organic solvents. Our work has extended the applicability of these crown ethers to the transport of salts from the solid state into solution both aqueous and nonaqueous. For this purpose a number of novel crown ethers have been synthesized that have in addition to a polar ‘cavity’ formed by donor atoms of the macrocyclic ring, (an) additional anionic functional group(s) covalently bound to the macroring.\ud \ud The first part of the lecture will deal with the design of such macrocycles that can encapsulate a spherical cation in a flexible cavity or that can encapsulate non-spherical cations. e.g. uronium cations, in a relatively rigid cavity.\ud \ud Together with the synthesis results of complexation studies using 1H NMR spectroscopy will be discussed.\ud \ud In the second part the use of crown ethers for the transport of sparingly soluble salts from the solid state into aqueous solutions will be dealt with. The emphasis will be placed on theoretical models that can be used to described such phase transfer processes and to predict thermodynamic stability constants of complexes required for solubilisation.\ud \ud The lecture will conclude with a comparison of these models with experimental results