18-Crown-6 ethers

Crown ethers are cyclic polyethers. Larger crown ethers contain a cavity that can partially engulf atomic ions. 18-crown-6 actually binds so tightly that it can extract this ion into benzene from water, driving counterions, like MnOc, into the benzene layer, i.e. 

Electrostatic potential map for 18-crown-6 shows negatively-charged regions (in red) and positively-charged regions (in blue). 

The crown conformation is not necessarily the most stable structure for free (uncomplexed) crown ethers. Examine the lowest energy structure of 18-crown-6, and compare it to the crown structure. Explain why the crown structure is less stable. Use equation (1) to calculate the equilibrium ratio of lowest-energy and crown conformers of 18-crown-6 at room temperature. What causes a shift in conformation in the presence of metal cations  

Although, like ethers, alcohols (ROH) also have an oxygen atom with lone pairs, they cannot be used to stabilize Grignard reagents, because alcohols possess acidic protons. 

As we saw in Section 13.6, Grignard reagents cannot be prepared in the presence of acidic protons. 

Gharles J. Pedersen, working for Du Pont, discovered that the interaction between ethers and metal ions is significantly stronger for compounds with multiple ether moieties. Such compounds are called polyethers. Pedersen prepared and investigated the properties of many cyclic polyethers, such as the following examples. Pedersen called them crown ethers because their molecular models resemble crowns. 

An electrostatic potential map of 18-crown-6 shows the oxygen atoms facing the inside of the internal cavity. 

A space-filling model of 18-crown-6 shows that a potassium cation can fit nicely inside the internal cavity. 

Chiral Crown Ethers. Perhaps the most extensive work in this area has been performed by Cram and his group, who utilize the chirality of 2,2 -binaphthol. Starting from optically pure materials, optically active crown ethers such as the (R,R)-macrocycles (55) can be synthesized, and these host molecules will form diastereo-meric complexes with the enantiomeric forms of chiral guest molecules, such as alkylammonium ions. For example, the more stable complex formed between 

Vdgtle and K. Frensch, Angew. Chem. Internat. Edn., 1976, 15, 685 F. Vogtle and B. Jansen, Tetrahedron Letters, 1976, 4895. 

Total resolution of aminoacid ester salts using this principle has been achieved by chromatographic methods, either liquid-liquid with (R,R)-(55a) in the mobile phase, or solid-liquid using either (R,R)-(55a) covalently attached to silica or the closely related ligand (55c) attached to a polystyrene resin through its hydroxyl group. In the latter method the observed complexation preferences at the resin- 

Further advances in this area are to be expected as there remains wide scope for exact tailoring of the host, etc., to different separation problems. Variations on the system of (55) - such as the inclusion of up to three binaphthyl units in a 24-membered ring, do not in general improve the enantiomer differentiation but may merely reduce the complexing ability of the system. 

Two research groups have prepared chiral crown ethers based on carbohydrate units as the source of chirality. Stoddart et al have synthesized systems (57) and (58) (and some aza-analogues) from L-tartaric acid and o-mannitol respectively, and have observed chiral recognition in liquid-liquid extractions to the extent of 60 40 enantiomer ratios from racemates when the R-group is bulky (57a), (58a) and with a-phenylethylamine as guest. Similar results were obtained with the mixed binaphthyl-mannitol ligand (59).  

Monobenzo- and dibenzocrown ethers are chlorosulfonated by reaction with a large excess of chlorosulfonic acid. Monobenzo-12-crown-4, -15-crown-5 and -18-crown-6-ethers, when treated dropwise with chlorosulfonic acid (10 equivalents) in chloroform solution at —10 to —5 C and the reaction mixture left at RT (five to six hours), gave the corresponding sulfonyl chlorides in 65-75% yield. For instance, monobenzo-12-crown-4-ether 498 afforded the chlorosulfonyl derivative 499. The orientation of sulfonation is, as expected, p to the electron-donating oxygen atom. 

Dibenzocrown ethers, namely dibenzo-18-crown-6 and -24-crown-8 by similar treatment with a larger excess of the reagent (20 equivalents) gave the corresponding disulfonyl chlorides. For example, dibenzo-18-crown-6 ether 500 afforded the disulfonyl chloride 501 as a mixture of stereoisomers, showing that chlorosulfonation of the dibenzocrown ethers does not occur regioselectively. The chlorosulfonyl and dichlorosulfonyl derivatives were converted into sulfonamides by reaction with ammonia and amines. 

Problem 18.15 15-Crown-5 and 12-crown-4 ethers complex Na and Li , respectively. Make models 

The first molecular mechanics studies of alkali metals were of the Na+, K+, Rb+ and Cs+ complexes of 18-crown-6 (Fig. 14.1)12551. The AMBER software system was used and the M+... 0 interactions were modeled using a combination of van der Waals 

There has also been a study of alkaline earth metal complexes of 18-crown-612601. In agreement with experiment, it was found that the selectivity in the presence of phosphate and water followed the order Ba2+ Sr2+ Ca2+ Ra2+ Mg2+12611. 

Their polar carbon-oxygen bonds and the presence of unshared electron pairs at oxygen contribute to the ability of ethers to form Lewis acid-Lewis base complexes with metal ions. 

The strength of this bonding depends on the kind of ether. Simple ethers form relatively weak complexes with metal ions. A major advance in the area came in 1967 when Charles J. Pedersen of Du Pont described the preparation and properties of a class of polyethers that form much more stable complexes with metal ions than do simple ethers. 

Pedersen prepared a series of macrocyclic polyethers, cyclic compounds containing four or more oxygens in a ring of 12 or more atoms. He called these compounds crown ethers, because their molecular models resemble crowns. Systematic nomenclature of crown ethers is somewhat cumbersome, and so Pedersen devised a shorthand description whereby the word crown is preceded by the total number of atoms in the ring and is followed by the number of oxygen atoms. 

12-Crown-4 and 18-crown-6 are a cyclic tetramer and hexamer, respectively, of repeating —OCH2CH2— units they are polyethers based on ethylene glycol (HOCH2CH2OH) as the parent alcohol. 

What organic compound mentioned earlier in this chapter is a cyclic dimer of —OCH2CH2— units  

Crown ether complexes of the -block metals number in the many hundreds, and reviews focused on them, including their use in separation chemistry and selective ion extractions, are extensive. Growing interest has been expressed in the use of macrocyclic ethers in the design of electroactive polymers.  

The 12-crown-4 ring is often complexed with lithium, and the sandwich [(12-crown-4)2Li] ion is common, although examples with and ions are known. 

The centrosymmetric dimer [Li(12-crown-4)]2, in which each lithium ion forms an intermole-cular Li—O bond with a neighboring crown ether molecule (Li—0 = 2.01 A) in a rectangular four-membered Li202 ring has been described.  

Molecular conductors have been constructed by using supramolecular cations as counterions to complex anions. For example, the charge-transfer salt Lio.6(15-crown-5)[Ni(dmit)2]2 H20 (dmit = 2-thioxo-l,3-dithiol-4,5-dithiolate) exhibits both electron and ion conductivity the stacks of the Ni complex provide a pathway for electron conduction, and stacks of the crown ethers provide channels for Li-ion motion. The /i-crown cation [Li(12-crown-4)](/i-12-crown-4) [Li(l2-crown-4)] has been generated as the counterion to [Ni(dmit)2]. The salt displays a room temperature conductivity of 30 S cm and exhibits a semiconductor-semiconductor phase transition on the application of pressure or on lowering the temperature. 

The 15-crown-5 ring binds a larger range of. s-block ions than does 12-crown-4, and simple [M(15-crown-5)] or [LnM(15-crown-5)]+ (L = H20, halide, ether, acetonitrile, etc.) complexes are common. Sandwich species of the form [(15-crown-5)2M] (M = Cs, Ba , ) are 

Charles John Pedersen (1904-1989) was born in Pusan, Korea, to a Korean mother and Norwegian father. A U.S. citizen, he moved to the United States in the early 1920s and received an M.Sc. at the Massachusetts Institute of Technology in 1927. He spent his entire scientific career at the OuPont Company (1927-1969) and received the 1987 Nobel Prize in chemistry. He is among a very small handful of Nobel Prize-winning scientists who never received a formal doctorate. 

An analogous picture is observed in the case of the alkaline earth metals [7]. For example, Ba +, of the same radius as K+, is the most suitable for the synthesis of LI245 (Eq. 6.4) [16]. 

Ions of diameter significantly smaller than that of the corresponding macrocyclic cavity are not effective for construction of the compounds of interest [12, 17J. However, these products can be synthesised in reasonable yield by using cations larger than the corresponding cavity size [12, 18-20]. The effectiveness of cations in assembling macrocycles is in one to one correspondence with their ability to form complexes with crown ethers, including those with a cavity size smaller than the metal ion diameter. 

In this case sodium(I) is the most eflFective for the synthesis of LI251, but potas-sium(I) provides the highest yield of L1252, L1253, L1256 and L1257. 

Lithiiun(I) is the best template for the synthesis of L1246, and sodium(l) in preparation of 24-crown-8 (LI259) for the reasons discussed above, although the same ligsons are involved as starting building blocks in the reaction (Eq. 6.6) (12], 

When considering the template-macrocycle match it is necessary to consider some unexpected cases, where crown ethers are formed having a cavity size that exceeds 

The quest for more methods in green chemistry, with benign reagents and by-products, catalytic cycles, and high yields, will no doubt drive further research by present and future chemists. In coming chapters we shall see more examples of green chemistry in use or under development. 

Crown ethers are compounds having structures like that of 18-crown-6, below. 18-Crown-6 is a cyclic oligomer of ethylene glycol. Crown ethers are named as x-crown-y, where x is the total number of atoms in the ring and y is the number of oxygen atoms. A key property of crown ethers is that they are able to bind cations, as shown below for 18-crown-6 and a potassium ion. 

Crown ethers render many salts soluble in nonpolar solvents. For this reason they are called phase transfer catalysts. When a crown ether coordinates with a metal cation it masks the ion with a hydrocarbon-like exterior. 18-Crown-6 coordinates very effectively with potassium ions because the cavity size is correct and because the six oxygen atoms are ideally situated to donate their electron pairs to the central ion in a Lewis acid-base complex. 

The relationship between a crown ether and the ion it binds is called a host-guest relationship. 

Salts such as KF, KCN, and potassium acetate can be transferred into aprotic solvents using catalytic amounts of 18-crown-6. Use of a crown ether with a nonpolar solvent can be very favorable for an Sn2 reaction because the nucleophile (such as F , CN , or acetate from the compounds just listed) is unencumbered by solvent in an aprotic solvent, while at the same time the cation is prevented by the crown ether from associating with the nucleophile. Dicyclohexano-18-crown-6 is another example of a phase transfer catalyst It is even more soluble in nonpolar solvents than 18-crown-6 due to its additional hydrocarbon groups. Phase transfer catalysts can also be used for reactions such as oxidations. (There are phase transfer catalysts that are not crown ethers, as well.) 

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Leigh D A, Moody A E, Wade F A, King T A, West D and Bahra G S 1995 Second harmonic generation from Langmuir-Blodgett films of fullerene-aza-crown ethers and their potassium ion complexes Langmuir 11 2334-6... 

The effects of the counterion on the reactivity of the enolates can be important Reactivity Li+ < Na+ < K+ < ITiN+ addition of crown ethers... 

Aryl, heteroaryl, and alkenyl cyanides are prepared by the reaction of halides[656-658] or triflates[659,660] with KCN or LiCN in DMF, HMPA, and THF. Addition of crown ethers[661] and alumina[662] promotes efficient aryl and alkenyl cyanation. lodobenzene is converted into benzonitrile (794) by the reaction of trimethylsiiyl cyanide in EtiN as a solvent. No reaction takes place with aryl bromides and chlorides[663]. The reaction was employed in an estradiol synthesis. The 3-hydroxy group in 796 was derived from the iodide 795 by converting it into a cyano group[664]. 

The intramolecular carbopalladation (or insertion) of the triple bond in dimethyl 4-pentynylmalonate (215) with Pd—H species and malonate anion as shown by 216 proceeds in the presence of f-BuOK and 18-crown ether, affording the methylenecyclopentane derivatives 217 and 218, the amounts of which depend on the reaction conditions. The Pd—H species may be formed... 

The metal-ion complexmg properties of crown ethers are clearly evident m their effects on the solubility and reactivity of ionic compounds m nonpolar media Potassium fluoride (KF) is ionic and practically insoluble m benzene alone but dissolves m it when 18 crown 6 is present This happens because of the electron distribution of 18 crown 6 as shown m Figure 16 2a The electrostatic potential surface consists of essentially two regions an electron rich interior associated with the oxygens and a hydrocarbon like exterior associated with the CH2 groups When KF is added to a solution of 18 crown 6 m benzene potassium ion (K ) interacts with the oxygens of the crown ether to form a Lewis acid Lewis base complex As can be seen m the space filling model of this... 

Since 1950 a number of polyether antibiotics have been discovered using fermentation technol ogy They are characterized by the presence of sev eral cyclic ether structural units as illustrated for the case of monensm in Figure 16 3a Monensin and other naturally occurring polyethers are similar to crown ethers in their ability to form stable complexes... 

In media such as water and alcohols fluoride ion is strongly solvated by hydro gen bonding and is neither very basic nor very nucleophilic On the other hand the poorly solvated or naked fluoride 10ns that are present when potassium fluoride dis solves m benzene m the presence of a crown ether are better able to express their anionic reactivity Thus alkyl halides react with potassium fluoride m benzene containing 18 crown 6 thereby providing a method for the preparation of otherwise difficultly acces sible alkyl fluorides... 

No reaction is observed when the process is carried out under comparable conditions but with the crown ether omitted... 

Ethers form Lewis acid Lewis base complexes with metal ions Certain cyclic polyethers called crown ethers, are particularly effective m coor dinatmg with Na" and K" and salts of these cations can be dissolved m nonpolar solvents when crown ethers are present Under these conditions the rates of many reactions that involve anions are accelerated... 

Phase transfer catalysis succeeds for two reasons First it provides a mechanism for introducing an anion into the medium that contains the reactive substrate More important the anion is introduced m a weakly solvated highly reactive state You ve already seen phase transfer catalysis m another form m Section 16 4 where the metal complexmg properties of crown ethers were described Crown ethers permit metal salts to dissolve m nonpolar solvents by surrounding the cation with a lipophilic cloak leav mg the anion free to react without the encumbrance of strong solvation forces... 

Critical micelle concentration (Section 19 5) Concentration above which substances such as salts of fatty acids aggre gate to form micelles in aqueous solution Crown ether (Section 16 4) A cyclic polyether that via lon-dipole attractive forces forms stable complexes with metal 10ns Such complexes along with their accompany mg anion are soluble in nonpolar solvents C terminus (Section 27 7) The amino acid at the end of a pep tide or protein chain that has its carboxyl group intact—that IS in which the carboxyl group is not part of a peptide bond Cumulated diene (Section 10 5) Diene of the type C=C=C in which a single carbon atom participates in double bonds with two others... 

Chips, semiconductor Chiral additives Chiral-AGP Chiral auxiliaries Chiral crown ethers Chiral hydrogenation Chirality... 

Fig. 9. An inclusion complex formed between a protonated primary amine and a chiral crown ether.

Cation Cation diameter, E Crown ether Cavity diameter, E... 

Fig. 7. Crown type and analogous receptor molecules of different varieties (1) crown ethers (2) cryptands (3) a podand (4) a spherand and (5) the natural...

The macrocychc hexaimine stmcture of Figure 19a forms a homodinuclear cryptate with Cu(I) (122), whereas crown ether boron receptors (Fig. 19b) have been appHed for the simultaneous and selective recognition of complementary cation—anion species such as potassium and fluoride (123) or ammonium and alkoxide ions (124) to yield a heterodinuclear complex (120). 

G. W. Gokel, Crown Ethers and Cyptands, Monographs in Supramolecular Chemisty, Vol. 3, The Royal Society of Chemistry, Cambfidge, 1991. 

Simple and Complex Organic Molecules. Using modem direct fluorination technology, the synthesis of even the most complex perfluorocarbon stmctures from hydrocarbon precursors is now possible. For example, syntheses of the first perfluoro crown ethers, perfluoro 18-crown-6, perfluoro 15-crown-5, and perfluoro 12-crown-4 (54) have been reported. Perfluoro crown ethers (54,55) are becoming important as the molecules of choice for many F-nmr imaging appHcations (56) in humans and are particularly effective in brain and spinal diagnostics when... 

Perfluoro crown ethers from the hydrocarbon dibenzo crown ethers have also been synthesized (58) and the first perfluorocryptand molecule [2.2.2] has been reported (59). The perfluorocryptand is a stable, inert, high boiling clear oil. 

Hydrocarbon crown ethers coordinate cations however, both the perfluoro crown ethers and the perfluorocryptands coordinate anions. For example, perfluoro crown ethers and perfluorocryptands tenaciously encapsulate O and F (60,61). 

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