I
A. C. Knipe School of Physical sciences The New University of Ulster Northern Ireland
I -
Crown Ethers A new aid to synthesis and to elucidation of reaction mechanisms
Manv of macrocvclic oolvethers (termed ~ . effective ~.. ~ svntheses ~ . . . ..crown" ethers l&ause of the appearanre ~f their m&cular rnotlrlsj develooed since C. .I. Pedersen reoorted ~ - ~, - haw ~ ~ - been ~ (1.2) on his pioneering work in 1967. There has been considerable interest in these compounds since they are capable of combining stoichiometrically with a variety of metal cations to form complexes which are stable both as crystalline solids and upon dissolution in a wide range of solvents. Recent reviews (3-5) have dealt with the synthesis of multidentate macrocyclic compounds and with their ion binding properties. Although there have been many recent and exciting devrlupments in the synthesis of t hese cornpuunds, no attempt will he mndr in this re\,iew, to update a comprchensi\,ecntahaue ( 4 ) of such nthie\wnent. The emphasis wiU alternatively heon successful application of macro&clic polyethers within the title areas. In the presence of crown ethers many ionic reagents are found to dissolve in solvents in which they would otherwise be insoluble (1,6-12) and to exhibit enhanced anion activity (13-18). The range of synthetic application of ionic reagents is thereby extended, and this has been particularly apparent in the development of two phase reactions (19-23) in which ion transfer is catalyzed by crown ethers. The influence of crown ethers on reactions believed to involve metal cationanion pairs has also been profitably explored (24-26) and interpretation of the dependence of reaction rate, stereochemistry, or specificity has, in several cases, clarified aspects of reaction mechanism (26-38). Macrocvclic have also been used to aid dissolu- ~olvethers . . tion of potassium and calcium metals in solvents in which it wns previously diffirult to study tiohfatedelectrons 139). Their applic~arimto pnhlrms of iunic transport in biological systems t m,.construction of ion sensitive elwtrodes (41 I, resolution of a-amino acids (42) or amines (43-47), interpretation of ion pair equilibria (48-531, and determination of free energies of transfer of anions (54) is further indication of their topical appeal. ~
~
~
~
~~~
~
~
~.
Structures (1)-(IV) are reoresentative of the manvmacro.. cyclic ethers that have beeniynhesized. The triviainomenrlnture introduced bv Pedersen ( 1 ) has been nodied wherehv each name consists bf, in order:'(i) the numi& and kind df hydrocarbon rings, (2) the total number of atoms in the polyether ring, (3) the class name, crown, and (4) the number of oxygen atoms in the polyether ring. The structure and chemistry of simple polyethen is of particular interest in view of their similarity to naturally occurring metabolites, such as nonactin (Va) and monactin (Vh), which also display cation selectivity. Their potential importance in the development C"?
R = H , nonactin I
-
Vb ; R = CH3, rnonactin of "host-guest" complexes which simulate the selectivity of enzymes has already heen emphasized (47). C"3
Synthesis of Crown Ethers
Condensation reactions have been widely employed to synthesize aromatic crown ethers in moderate to high yields (1,2,4) according to the following and related schemes, where X is a suitable leaving group (e.g. C1 or OTs)
-
aO(CH&Ha).CH2CH0
+ 4NaX + 4Hs0
O(CH,CH,O).CH,CH,O Corresponding saturated crown ethers can subsequently he obtained upon hydrogenation, catalyzed by ruthenium. Crown ethers containing one or more sulfur or nitrogen atoms in place of oxygen have likewise been prepared and syntheses and applications of bicyclic and polycyclic polyethers are also being explored (55-57). Compounds (VIa-f) are illustrative of such structures.
Properties of Crown Ethers
f
N
0
The aromatic polyethers are colorless crystalline compounds, which are readily soluble in chloroform or methylene chloride but are insoluble in water and only sparingly soluble 618 / Journal of Chemical Education
in many other solvents at room temperature. They can be modified by the usual range of reactions of aromatic compounds and can often he purified by distillation. The saturated polyethers are liquids or low melting solids and are appreciably soluble in a wide range of solvents from water to net. ether. ~rown.ethersreadily form complexes with the cations of alkali and alkaline earth metals and also with Ae+. An+. Zn2+. ad a feu; c ~ z +~, g +~, g z +TP+, , ~ e 3 +pb2+, , N H ~ +RNH;+ , transition metals. 0ne:one complexes (e.g. (VII), (Pig. I)), in which the cation is electrostatically hound to the electronegative oxveen atoms. are most stable for those ethers containine 5-10 oxygen atoms, each separated from the next by two carbon atoms. Well defined crvstalline comolexes of 21 and 3:2 stoichiomatry (polyether:sali) have also heen prepared (61) hv simple procedures, the stoichiometrv and stabilitv of each c,rmpl&x\;.ing dependent upon: ( 1 ) the relative si& of the i m and rhf: hole in the rwkether ring; (2)theelectriralchar~e on the ion; (3) the tendency of thelon to associate with the solvent, and (4) the number, coplanaritv, symmetry, basicity, and steric environment of the oxygen atoms in the ring. Stability constants (e.g. K1 and K2 as defined hy'eqns. (1) and (2)) have been determined for many crown ether (C) complexes (see Table VIII of ref. (4); (62,63)) including those represented in Table (1)
Typically the stability constants ( K , ) for polyether-cation complexes go through a maximum as the size of the alkali metal cation increases (see Table 1). Likewise the stability constant for each cation may go through a maximum with increasing polvether ring size as the optimum hole size for c~mplexationis approached nnd excee&d. iandu,ich structures 1'21, have been ohtined (611in cases where the cation is too large to be accommodated by a single polyether molecule whereas, by analogy with macrocyclic antibiotics (66), large flexible polyethers or bicyclic ethers (67) may completely envelop cations. The 21 sandwich (VIII) and the complex cation (1x1 are illustrative of such forms. Structures (V1I)-(1x1 have been established by X-ray crystallography (58-60) and a compendium of further cryptate structures is available (see Table IX of ref. (4)). There has, of course, been considerable interest (47) in "tailor made" macroheterocycles designed to preferentially comolex certain metal ions and onium ions. Cram and his ccworktri havr, for rxnmple, attempted (63) ro modify the :~w,ciationconstanti of pol?.pthers S by systematic variation
of R and n (R = C02CH3, H, CH20CH3,CH20H, C02H, CN; n = 2-71 and there is clear indication that these inner directed 2-substitnents of the 13-xylyl units can act as additional ,binding (and possibly catalytic) sites. Applications of Crown Ethers
The application of cyclic polyethers to organic chemistry depends largely upon their stability and appreciable solubility in a wide range of solvents combined with their ability to (1) enhance solubilities of many metal salts in organic solvents and (2) increase activities of the co-anion as a direct result of complexation of the cation.
F i v e 1. Some crown ethar complexes. VII, NaB(dicdicyclohexy1-~EcTow~), ref. 158);VIII, Complex cation of Kl(benr~l5aownd), ref. (59): IX. Camplex cation of Kl(d1benzo-30-crown-lo), ref. (60).
Table 1. Stability Constants (64, 651 for 1 : l Complexation of Dicvclohexvl-[la]-Crown 6 Ether With Cations at 25'C
H P MeOH
LC+
~ a +
K+
0.6
1.7 4.1
2.2 6.0
~ b + 1.5
cr+
NH,+
~
1.2
1.4
2.3
g
+
4.6
Enhanced Solubility of Reagents In the presence of dicyclohexyl-[la]-crown-6 it is possible to dissolve ootassium hvdroxide in benzene a t concentrations in excess oi0.15 M. he free hydroxide ion is very reactive in this medium and is capable ( I ) of hydrolyzing alkyl esters of 2,4,6-trimethyl henzoic acid which are normally resistant to saponification in hydroxylic solvents. Potassium permanganate can likewise he solubilized in benzene and has been found to oxidize alkenes, alcohols, aldehvdes. and alkvl benzenes undrr theye mild nunaqurou> neutral renditions 161. The ch~lationaction of crown ethers has also heen used to render organopotassium compounds soluble in nonpolar media and to permit investieation of vewreactive carbanions in solutions where they are largely unperhhed by the counter ion. Thus, organopotassium ions have been generated (7) by the diimide route in presence of dicyclohexyl-[18]-crown-6, e.g.
-
ArN=NCOz-Kt Ar-K+ + N2+ Cog. The soluhilization of KF in acetonitrile and benzene containing 18-crown4 to give "naked" fluoride ion has been used to advantage ( 9 ) .Under such conditions, wherein the ion acts as a potent nucleophile and base, the following reactions can be achieved: (1) displacement of leaving groups attached to sp3 hybridized carbon at primary, secondary, tertiary, or benzylic positions; (2) displacement of leaving groups from sp2 hybridized carbon and (3) elimination. Enhanced soluhilitv and reactivitv of KI. KBr. and KOMe have also been reported (IO),and kinetic data for substitution reactions of n-butvl brosvlate in acetone reveal that the complexed potassi"m halides are more reactive than either the corresponding tetrahutvlammoninm halides or LiBr. Reaction of croGcomplexed KOMe with o - and m-dichlorobenzene a t 9OoC, to give the corresponding chloroanisole, constitutes a rare example (10) of a nucleophilic aromatic substitution of an unactivated aromatic halide hv MeO-. l97%) to cis-alkene (87%) formation is observed, as the almost exclusive syn-specificity of the ion pairs gives way to predominant anti-elimination by Bu'O-. This technique has also been used (29) to identify the role of contact BuiO-K+ ions in the reaction of (XVIII) to give cisand trans-((XIX) and (XX)). The crown ether causes com-
of crown ether their absolute values are very much less and kJk, = 46. The crown ether, bv occu~vinethe coordination sites-of potassium ion, prevents the c&xffrom ordering the orientation of entering and leaving groups on the front face of the carbanion intermediate and thereby prevents a retention mechanism. Similar results have been reported for deprotonation of indenes (24) and for the exchange reaction (-)-(XXI1)-H (XXI1)-D,where kJkm is reduced from 21 to 0.8 upon addition of dicyclohexyl-[la]-crown-6to the ButOK-ButOD system (32). The differential influence of crown ether complexation on com~etine reaction ~ a t h w a v sis revealed bv the isomer dis. trihutions of the prdduct alcohols ohtainedin the reduction of substituted cvclohexanones. with sodium borohvdride in toluene (331, and by the tendency of acetoacetic este; enolates to undergo less O-alkylation in the presence of a crown ether especially in weakly polar solvents (34). The effect of the gegenion on the conformational preference of 0-diketone enorates has also been determined (35) from the [la]-crown4 dependence of the nmr spectrum of sodium acetylacetonate in pyridine-d6. A crown ether has also been employed in the elucidation of the origin of high ortholpara reactivity ratios in the reactions of fluoronitrohenzenes with potassium t-butoxide in t-butyl alcohol (36). The high ratio has thus been attributed to specific stabilization of the transition state for reaction of the ortho-nitro com~oundhv potassium ion brideine " " between the nucleophile and the nitidgroup. In the presence of dicyclohexyl-18-crown-6 the potassium ion is complexed and the ortho/para ratio is close to unity. Crown ether complexation has recentlv facilitated interpretation of the different selectivity, towards alkenes, exhihited hy phenylbromocarbene generated alternatively by treatment of henzal bromide with Bu1OK or by photolysis of phenylhromodiazirine (37). In view of the differing selectivities revealed in Table 2, columns a and h, it has been assumed that the former procedure gives rise to a carhenoid complex, between the phenyl halocarbene and either potassium helide or ButOK, while the latter proceeds via a free carhene. This view is sunnorted hv the observation that the olefin selectivitv .. (column c) of the carhene generated (presumably uncomnlexed). hv addition of benzal bromide to homoeeneous alkene-benzene solutions of 1:l ~ u ~ 0 ~ / 1 8 - c r o w n -identical 6k to that of the ~hotochemicallv carbene. Thus. crown . eenerated " ethers may play an important role in the investigation of carbene versus carbenoid reactivitv. This work has recentlv beep extended (38)to include generation and study of free PhCF and CH&CI.
-
-
plete reversal of the trans-/cis-alkene ratios in both Bn'OH and benzene but has less effect in DMF. The importance of base association on the stereochemistry of base promoted &eliminations from norbornyl derivatives has also been established (30). Metal cations have also been shown to control the stereochemical fate ofoirhanions generated by metal alknxldrs in alcoholic media. l'hus, in the Dresence uf dic\~clohex\~I-I181... crown-6 the rates of deuterium exchange (k,jand racemization (k,) of (-)-(XXI) are equal (31) whereas in the Absence
Conclusion
I t has become increasinelv clear that metal cations often have an influence on the ac%ity and reactions of their coanions, even in relatively polar solvents, and this may generally be ascribed to ion pair association. Consequently, the products and/or rates of such reactions mav be altered in the presence of reagents which modify the cooidination sphere of the cation; such effects can, of course, be used to synthetic and mechanistic advantage. Table 2. Reactivities of Alkener lil. Relative t o That of Tetramethylethylene I T M E ) , Toward Phenylbromacarbene at 25%
trimethylethylene irobutene eis-butene trans-butene irobutened
1.28 1.65 5.79 11.3 2.6
1.74
4.44 8.34 17.5
5.0
1.72 4.11 8.24 17.1 4.8
See ref. 137) for error limits etc. ~ ( X X I I I +) B U ~ O K . ~IXXIV+ ) hv. C ( X X l l l ) + B u f O ~ +18-Crown-6. d Reactions were of the ch~orocarbene.
Volume 53,Number 10, October 1976 / 621
This has prompted the recent development of macrocyclic polyethers and related compounds which exhibit high specificity in their coordination with cations, chemical stability towards many anionic reagents, and reasonably high solubility in common solvents. Several crown ethers are now available commercially and some can he prepared by straightforward procedures. It is not surprising, therefore, that during the past few years there has been a marked increase in the number of reports of effective annlication of crown ethers. Their value in elucida.. tion of the role of ion pairs in reaction mechanisms has been oarticularlv noticeable. I t is now clear that such compounds will have an increasingly important role to play and it is hoped that this brief review of their novel chemistrvmav . . encourape this development. While macrocvclic polvether chemistry has a current a ~ ~ e a l for most chemists I feelthat educationalists should pay particular attention to this topical area. Crown ether chemistry can he efferti\.elv incorporated within a curriculun~as a vrhicle fiw the incearatrd approach. Thus, fundamental orannic reactions, inherent in their synthesis and properties, can be presented alongside the physical principles of solvation equilibria and ion pairing. The coordination of metal ions can then be discussed with reference to ionic radii, charge density, and ligand structure. It can then he illustrated that by combined application of physical, organic, and inorganic principles it has been possible to tailor make macro-molecules whose selective coordinating ability can be used to great advantage. Literature Cited 11 1 Pederren. C. d.. J . Amer Chem Soc.. 89.7017 119671. I21 1'edersen.C.J.. J. A m e i Cham. Soc., 89.2&95 119671. (:I1 Ped~rsen.C. J.. and Fmnsdorff. H. K.. Anpew. Chem Inf. Edn., 11.16 (1972). 141 Christenren..l. J.. Eatuugh, D. J.,snd 1zstt.R. M.,Chem. Re". 74.351 (1974). 161 Twter,M. R..andPedenen,C.J.,Endeavuur30,142 11971):Chrirtensen,J.J. .I. 0 . a n d 1zstt.R. M.,.Teienee. 174.459 l197l). 181 Sam. D.J.. and Slmmona H. E. J. A m m Chem. Soc.. 94.4024 119721. . . 171 ~ r n ~ n t and e~. id, ~ . . T e t ~ ~ h ~LPII.. d ~ 133 o n 1i9701. 18) Durst. H. D.. Zubrick. J . W., and Klecrykowski, G. R., Tetrahedron Lett., 1777 ,,w4>
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,.
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