Synthesis of Crown Ethers

Synthesis of Crown Ethers. - The fundamental approach to the syntheses (cyclization by nucleophilic substitution of the separate halves of the ring) remains unchanged. The metal-catalysed cyclization of (60) to form benzo- 

18-crown-6 has been studied, and the catalytic effects of both alkali-metal and alkaline-earth cations in methanol have been measured. The observed acceleration ranged from 13.2 for Cs to 540 for Sr. The differences in catalytic effect were attributed to a combination of the proximity of the reactive ends of (60) and the extent of interaction between the cation and the oxide anion. Similar template effects were observed in the condensation of diethyl malonate and ethylene glycol to give 1,4,8,11-tetraoxacyclotetra-decane-5,7,12,14-tetraone.  

The crown ethers (61) have been synthesized by a novel Dieckmann condensation of the diester (62) under high dilution. The ester and ketone groups are readily removed. 

A number of intriguing crown ethers have been prepared by conventional routes, including a derivative of 18-crown-6 that bears a trans double bond and the first crowned redox system (63). ° The hydroxylated crown ethers 

Sugihara, H. Kamiya, M. Yamaguchi, T. Kaneda, and S. Misumi, Tetrahedron Lett., 1981,22, 1619. 

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Numerous other methods exist for making the simple crowns. Many of these methods are compared in Sect. 3.1 which deals with variations in the synthesis of 18-crown-6. Further commentary on the influence of templating ions on the synthesis of crown ethers may be found in Chap. 2, which deals with various aspects of the template effect. 

Schroder and Witt ° have reported the synthesis of crown ethers having fluctuating ring sizes which they have termed breathing crown ethers . The structures are based on the bullvalene subunit and, as the tetracyclic subunit undergoes Cope rearrangement, the size of the macroring likewise varies. The synthetic steps follow the conventional routes used for the preparation of crown ethers and are illustrated in Eq. (3.44). 

Okahara and his coworkers have made a number of contributions to the synthesis of crown ethers using a one-pot method (see Sect. 3.13). These methods have been applied largely to the preparation of simple aliphatic crown ether systems. In addition, this group has prepared macrocyclic ester compounds using a one-pot procedure. Although... 

Design and synthesis of crown ethers and other macroheterocycles as highly selective ionophores for chemical ion sensors 98YGK291. 

Immobilization of phase-transfer catalysts on polymeric matrices avoids the problem of separating and recycling the catalysts. In this case the chemical stability of the immobilized catalyst becomes very important quaternary salts often decompose under drastic reaction conditions whereas polydentate ligands are always stable. However, the difficult synthesis of cryptands, despite their high catalytic efficiency, can hardly justify their use. Synthesis of crown-ethers is much easier, but catalytic efficiences are often too low. 

Okahara and coworkers have developed a one-step cyclization of oligoethylene glycol ( 1, 19) and applied it to the convenient synthesis of crown ethers with higher alkyl chains (, 21). 

The various strategies available for the synthesis of crown ethers have been analyzed (12, 17-19, 43) and reviewed (1-10, 20) at considerable length. In principle, the problem of introducing chirality into crown compounds can be tackled in three different ways. 

Under high dilution conditions (81JCR(S)314) bis-acyl chlorides react with diols to generate the corresponding tetralactones (41) (77TL2573). This procedure has most commonly been applied to the synthesis of crown ethers with subunits (79CRV37). Lactams have been prepared similarly from suitable diamines (76TL2603). 

The parent glycols have also been studied, particularly in solution and in connection with their possible role in the template synthesis of crown ethers.33 Crystalline complexes have been isolated in certain instances and the structures of Ca(picrate)2-glycol-5-F O,207 Sr(NCS)2-glycol-8208 and Sr(NCS)2-glycol-7209 have been solved. (Glycol-5 is H0(CH2CH20) H, n = 4, etc.) The Sr2+ complexes show the metal to be coordinated by the... 

Liquid-liquid PTC would seem to be convenient for the synthesis of crown ethers and derivatives. But most still use conventional conditions,28,29 probably because the synthesis of macrocyclic crown ethers gives better results when Na+ or K+ ions are involved. These ions can induce a template effect with the polyethyleneoxy chain 63. 

Scheme 2 Solid-Phase Synthesis of Crown Ether Modified Peptides 14 ...

Synthesis of Crown Ether Lysine and Glutamic Acid Derivatives... 

The present chapter will not deal with general topics of liquid crystals or crown ethers as this exceeds the scope of this volume. Interesting reviews and monographs on liquid crystals and their properties can be found in the literature [10-13]. The synthesis of crown ethers can be challenging. Most commonly, the synthetic routes are based on procedures established by Pedersen [14-17]. A review by Bradshaw [18] and a monograph edited by Patai [19] also cover the synthesis and properties of crown ethers. More recent reviews deal with the use of crown ethers as chemosensors [20, 21], potential antitumor agents [22], molecular wires [23], or carriers for the separation of metal ions in liquid membrane processes [24],... 

The synthesis of crown ethers in 1967 fortunately occurred about the same time as naturally occurring lipophilic metal-binding agents were being identified as products of microbial growth. As the literature on synthetic and natural product ionophores is extensive274,275), there is no justification for a discussion on their chemistry here. 

An effective template metal ion binds strongly to the donor atoms of the macrocycle or its precursors, e.g., K+ is the most common template for synthesis of crown ethers and forms definite complexes with a wide variety of crown ethers. 

In addition to classical substituents such as NH2, NHR, NR2, OR, SR in various combinations, in recent years some more exotic groups have been attached to phosphazene rings. Among the novel cyclic phosphazenes the carbo-rane substituted derivatives are worth mentioning. Other unusual derivatives include chiral cyclophosphazenes, cyano-, ferrocenylphenoxy-, and ferrocenylhydrazone-cyclophosphazenes. Another interesting development is the synthesis of crown ethers with chlorocyclophosphazene subunits (Scheme 54). ... 

Synthesis of crown ether bislactones using caesium carboxylates of pyridine and of benzene dicarboxylic acids, O. Piepers and R. M. Kellog, J. Chem. Soc., Chem. Commun., 1978, 383. 

The conformational preference, leading to the formation of rings of a certain size, has ingeniously been used by Dale for the synthesis of crown ethers of a desired ring size by the cationic polymerization of ethylene oxide 24). The principle of this method is based on the folding of the chain-end around a purposely introduced cation solvated specifically by a well-defined number of ethylene oxide units (cf. also Sect. 4.2.2.1) ... 

Carbohydrates have often been applied as starting materials for the synthesis of crown ethers, as they already contain hydroxy functions which are easy to incorporate in the crown ether structures. Crown ethers derived from commercial disaccharide D-lactose (7) have been used for the catalysis of the Michael addition. Benzyl 2,3,2 -tri-0-benzyl-3, 4 -0-isopropylidene-6,6 -0-(3,6,9-trioxaundccane-1,1 l-diyl)-/ -lactoside (8) was prepared by careful use of protection and benzyla-tion techniques as outlined11 similar crown ethers, e.g., 9, were obtained by analogous techniques12 13. 

In the context of crown ether hosts, non-covalent bonds of pole-pole, pole-dipole, and dipole-dipole types can all be employed [3-6] in the formation of host-guest complexes. Where the guest species is an alkali metal (i.e. Li, Na", K", Rb, Cs ), alkaline earth metal (i.e. Mg, Ca, Sr, Ba ), or harder transition or post-transition metal (e.g. Ag", TT, Hg, Pb, La, Ce ) cation [3-6,14], an electrostatic (M" O) pole-dipole interaction binds the guest to the host whilst the (M" X ) pole-pole interaction with the counterion (X ) is often retained. The features are exemplified by the X-ray crystal structure [15] shown in Fig. la for the 1 2 complex (1) (NaPF jj formed between dibenzo-36-crown-12 (1) and NaPF. Molecular complexes involving metal cations have considerable strengths even in aqueous solution and a template effect involving the metal cation is often observed during the synthesis of crown ether derivatives. 

Reactions.- Crown lactones are reduced to the corresponding crown ether on reaction with LiAlH at 0°C. The procedure may allow the synthesis of crown ethers which are inaccessible by the Williamson ether synthesis. The reduction of 2,6-pyrido-18-crown-6 N-oxide by (CH CHCHgCH BH appears to involve a single electron transfer as the rate-determining step, followed by transfer of a... 

Another celebrated example of the template effect is the synthesis of crown ethers by Pedersen [11], but it was Busch who first intentionally used templates in synthesis and who first articulated the concept of the template effect in the 1960s [12]. Busch used the reaction of a nickel(Il) dithiolate complex 7 with l,2-bis(bromomethyl)benzene 8 to illustrate his ideas (Scheme 1-3) [13]. Once one end of the l,2-bis(bromomethyl)ben-zene has reacted with the nickel complex, the nickel template induces the reactive ends of the intermediate 9 to come into close proximity and favors cyclization. The metal template allows the synthesis of a metallated macrocycle 10 the free ligand cannot be prepared by the reaction of l,2-bis(bromomethyl)benzene with the unbound thiol (in the absence of a template other cyclic and acyclic products are formed). 

Synthesis. A new general synthesis of crown ethers involves treatment of polyethylene glycols with sulfonyl chlorides in the presence of NaOH or KOH, which serves as the template. For example, 15-crown-5 was obtained in 50% isolated yield by this method (equation I). 18-Crown-6 is prepared in this way in 757 yield. Substituted crown ethers have also been prepared by this method. 

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