Polyethylene crowns

Pins polystyrene- or polymethacrylamide-dimethylacrylamide-fcopolymerised) derived matrices grafted on polyethylen crowns which arc attached on top of pins. The pins usually are assembled in the typical 96-well plate format. This technology originally developed by Geysen et a/.. 57.5S for the parallel synthesis of polypetide libraries has found wide applications also for the synthesis of small-molecular-weight compound collections... 

The first method is shown in Eq. (3.1). This corresponds to the so-called one plus one synthesis of crowns. The notion is that a single diol unit is allowed to react with a single polyethylene glycol having leaving groups at each end. An example of this would be the synthesis of benzo-15-crown-5 from catechol and tetraethylene glycol dichloride. Note that the stoichiometry of this method is identical to that of method X which is shown below in Eq. (3.3). 

Reinhoudt, Gray, Smit and Veenstra prepared a number of monomer and dimer crowns based on a variety of substituted xylylene units. They first conducted the reaction of 1,2-dibromomethylbenzene and a polyethylene glycol with sodium hydride or potassium Z-butoxide in toluene solution. Mixtures of the 1 1 and 2 2 (monomer and dimer) products were isolated and some polymer was formed . The reaction was conducted at temperatures from 30—60° and appeared to be complete in a maximum of one hour. The authors noted that the highest yield of 1 1 cyclic product was obtained with disodium tetraethylene glycolate instead of dipotassium hexaethylene gly-colate (see also Chap. 2) . Chloromethylation of 1,3-benzodioxole followed by reaction with disodium tetraethylene glycolate afforded the macrocycle (29% yield) illustrated in Eq. (3.20). 

With the discovery of the crowns and related species, it was inevitable that a search would begin for simpler and simpler relatives which might be useful in similar applications. Perhaps these compounds would be easier and more economical to prepare and ultimately, of course, better in one respect or another than the molecules which inspired the research. In particular, the collateral developments of crown ether chemistry and phase transfer catalysis fostered an interest in utilizing the readily available polyethylene glycol mono- or dimethyl ethers as catalysts for such reactions. Although there is considerable literature in this area, much of it relates to the use of simple polyethylene glycols in phase transfer processes. Since our main concern in this monograph is with novel structures, we will discuss these simple examples further only briefly, below. 

It was noted early by Smid and his coworkers that open-chained polyethylene glycol type compounds bind alkali metals much as the crowns do, but with considerably lower binding constants. This suggested that such materials could be substituted for crown ethers in phase transfer catalytic reactions where a larger amount of the more economical material could effect the transformation just as effectively as more expensive cyclic ethers. Knbchel and coworkers demonstrated the application of open-chained crown ether equivalents in 1975 . Recently, a number of applications have been published in which simple polyethylene glycols are substituted for crowns . These include nucleophilic substitution reactions, as well as solubilization of arenediazonium cations . Glymes have also been bound into polymer backbones for use as catalysts " " . 

Tetrasubstituted phosphonium halides are just as effective as their ammonium counterparts. A combination of tetraphenylphosphonium bromide and either 18-crown-6 or polyethylene glycol dimethyl ether with spray-dried potassium fluoride converts 4-chlorobenzaldehyde to 4-fluorobenzaldehyde in 74% yield [67] In addition, the halogen of a primary alkyl chloride or bromide is easily displaced by fluorine in aqueous saturated potassium fluoride and a catalytic amount of hexadecyltributylphosphonium bromide [68] (Table 7 Procedure 4, p 194)... 

Cyclic polyethylene oxides) ( Crown ethers ), Potassium hydroxide Le Goaller, R. etal., Synth. Comm., 1982, 12, 1163-1169 Crown ethers promote dihalocarbene formation from chloroform or bromoform and potassium hydroxide. However, in absence of diluent dichloromethane, dropwise addition of bromoform to the base in cyclohexane led to explosions. 

However, other polymer composite materials also popular in solid-phase synthesis, such as polyethylene or polypropylene tea bags , lanterns, crowns, or plugs, are generally less suitable for high-temperature reactions (>160 °C). Therefore, micro-wave irradiation is typically not a very suitable tool to speed up reactions that utilize these materials as either a solid support or as containment for the solid support. 

Since polyethylene glycols and glymes of low molecular weight are very hydrophilic, it is not surprising that they are often less active than crown ethers in liquid-liquid systems (Movsumzade et al., 1976). High-molecular-weight... 

It was a result of demand from industry in the mid-1960s for an alternative to be found for the expensive traditional synthetic procedures that led to the evolution of phase-transfer catalysis in which hydrophilic anions could be transferred into an organic medium. Several phase-transfer catalysts are available quaternary ammonium, phosphonium and arsonium salts, crown ethers, cryptands and polyethylene glycols. Of these, the quaternary ammonium salts are the most versatile and, compared with the crown ethers, which have many applications, they have the advantage of being relatively cheap, stable and non-toxic [1, 2]. Additionally, comparisons of the efficiencies of the various catalysts have shown that the ammonium salts are superior to the crown ethers and polyethylene glycols and comparable with the cryptands [e.g. 3, 4], which have fewer proven applications and require higher... 

Polymer phase-transfer catalysts (also referred to as triphase catalysts) are useful in bringing about reaction between a water-soluble reactant and a water-insoluble reactant [Akelah and Sherrington, 1983 Ford and Tomoi, 1984 Regen, 1979 Tomoi and Ford, 1988], Polymer phase transfer catalysts (usually insoluble) act as the meeting place for two immiscible reactants. For example, the reaction between sodium cyanide (aqueous phase) and 1-bromooctane (organic phase) proceeds at an accelerated rate in the presence of polymeric quaternary ammonium salts such as XXXIX [Regen, 1975, 1976]. Besides the ammonium salts, polymeric phosphonium salts, crown ethers and cryptates, polyethylene oxide), and quaternized polyethylenimine have been studied as phase-transfer catalysts [Hirao et al., 1978 Ishiwatari et al., 1980 Molinari et al., 1977 Tundo, 1978]. 

Bromo substituents in the 6- and 6 -positions of 2,2 -bipyridines are particularly reactive, being readily converted to amino,cyano, ° al-koxyl, hydrazino, chloro, and hydrogen groups and by way of the corresponding lithio derivatives to carboxyl, methyl, aldehyde or alkylcarbonyl, and other groupings. 6,6 -Dibromo-2,2 -bi-pyridine also reacts with the disodium derivatives of polyethylene glycols to give crown ethers akin to 100, and 6,6 -bis(chloromethyl)-2,2 -bi-pyridine " and the derived 6,6 -bis(mercaptomethyl)-2,2 -bipyridine... 

Crown ether, cryptand, and poly(ethylene glycol) catalysts are more stable in base than the quaternary ammonium and phosphonium ions. Only the polyethylene glycols) are likely to meet industrial requirements for low cost, although a number of more efficient, lower cost crown ether syntheses have appeared recently, such as those of sila-crowns 64 bound to silica1B9). 

Polyethers. Polyethers such as polyethylene oxide (PEO) and polypropylene oxide (PPO) have been used for ESI-MS calibration [10,11,19]. The predominant ions for these calibrants are cation attachments, and sodium attachment is frequently observed, due to traces of sodium in solvents and glassware. The positive-ion ESI mass spectra of PEO and PPO are characterized by abundant [M + nNa]n+ and some [M + ] + species. Macrocyclic polyethers and crown ethers were also used as ESI-MS calibrants [11]. In general, nonderivatized polyethers show the following drawbacks when used as calibrations solutions (1) they are difficult to flush out of the ion source, (2) they generate complex mass spectra resulting from the presence of several different cation sources, and... 

Although acyclic polyethers, e.g., polyethylene glycols, form less stable solvates than the cyclic counterparts, they are also able to act as catalysts in biphasic systems. Typical structures of open-chain equivalents of crown ethers and cryptates are glymes32-34 (3) polyethylenamines35,36 (4) poly-podes37,38 (5) lariat ethers39,40 (6) and octopus41 (7). 

Linear polystyrene can be generated on insoluble polymers by /-irradiation of the latter in a solution of styrene [110]. Polystyrene grafted onto polytetrafluoroethylene [111-116], polyethylene [2,110,117], or polypropylene [15] can be functionalized in the same way as cross-linked polystyrene, and loadings of up to 1.0 mmol/g can be attained. These supports, which are also available as crown-shaped pins (Multipin, 2-3 mm diameter, 8-10 pmol per crown), have been used for the synthesis of peptides [2,110,111,118], oligonucleotides [112-115,117,119], and small molecules [120-122]. 

Polyethylene has been grafted with acrylic acid, 2-hydroxyethyl methacrylate//V,/V-dimethylacrylamide, or methacrylic acid//V,/V-dimethylacrylamide to yield supports (e.g. Figure 2.10) suitable for the synthesis of peptides [2,222-224] and other compounds [216,225,226]. A similar support, also suitable for the synthesis of peptides, is polypropylene grafted with hydroxypropyl acrylate [227]. These supports can be used as membranes or as crown-shaped pinheads (Multipin 2-4 mm diameter) with loadings of 1.2-2.2 pmol per crown. 

---