18-Crown-6

[17455-13-9]  · C12H24O6  · 18-Crown-6  · (MW 264.32)

(solubilization of a variety of metal salts, particularly potassium salts, in nonpolar solvents; activating agent for many nucleophilic substitutions and eliminations)

Physical Data: colorless, mp 36.5-38.0 °C; IR (neat) 2875, 1450, 1350, and 1120 cm-1; 1H NMR (60 MHz, CCl4) 3.56 ppm (singlet).

Preparative Methods: commercially available. 18-Crown-6 has been synthesized by a variety of methods involving modified Williamson ether procedures.1-6 Crude 18-crown-6 forms a crystalline complex with Acetonitrile from which the pure crown can be isolated.4,5 18-Crown-6 may also be isolated from the cyclic oligomerization of Ethylene Oxide in the presence of gaseous Boron Trifluoride and alkali metal cation templates such as CsBF4.7-10

Handling, Storage, and Precautions: use in a fume hood.

Complexation with Metal Salts: Solubilities and Reactivities.

18-Crown-6 provides a simple and efficient means of solubilizing simple metal salts in nonpolar and dipolar aprotic solvents where solvation of the anionic portion of the salt should be minimal.11 Indeed, this ligand is an effective catalyst in liquid-liquid and solid-liquid phase transfer catalysis.12-14 Since 18-crown-6 has cavity dimensions (2.6-3.2 Å) of the same magnitude as the ionic diameter of the potassium cation (2.66 Å), it is usually more specific for potassium salts than other alkali metal salts. Nevertheless, 18-crown-6 is reasonably effective in complexing sodium and cesium salts as well. The solubilities of potassium salts in acetonitrile at 25 °C in the presence and absence of 18-crown-6 (0.15 M) are summarized in Table 1.11

The differences between the solubilities in the presence and the absence of crown are indications of the solubility enhancements due to the presence of 18-crown-6. The solubilities of Potassium Fluoride in benzene containing 18-crown-6 at concentrations of 1.01 M and 0.34 M are reported to be 0.052 M and 0.014 M, respectively, while the solubilities of potassium acetate in benzene containing 18-crown-6 at concentrations of 0.55 M and 1.0 M are reported to be 0.4 M and 0.8 M, respectively.11 The solubilities of Lithium Fluoride, Sodium Fluoride, KF, RbF, and Cesium Fluoride in acetonitrile, Acetone, THF, N,N-Dimethylformamide, benzene, and cyclohexane have been determined in the presence and absence of 18-crown-6.15

The complexation and solubilization of metal salts by 18-crown-6 produces highly reactive anions. There are at least two factors that contribute the this enhanced reactivity. Since a nonpolar aprotic solvent such as benzene or a dipolar aprotic solvent such as acetonitrile should not have a great affinity for the anion, as compared to polar, protic media, the anion is not expected to be highly solvated. In addition, the increased physical separation of the cation from the anion as a result of the complexation should decrease the coulombic interaction between these oppositely charged species.13 This latter effect is translated directly into a decrease in activation energy. As a consequence, the anion is a potent nucleophile as well as a potent base. These anionic species have been termed naked anions. Studies related to the relative nucleophilicities of naked anions toward benzyl tosylate in acetonitrile at 30 °C are summarized in Table 2.11,13,16 Compared to polar, protic media, there seems to be a general leveling of nucleophilicities in acetonitrile. Several reversals of the usual order of nucleophilicities may be noted.

Reactions.

Halides.

Potassium fluoride reacts with a variety of organic substrates under solid-liquid phase transfer catalytic conditions17 to give both substitution and elimination products (eq 1).

The s-anionic complex (Meisenheimer complex) resulting from the reaction of fluoride with 2,4,6-trinitrofluorobenzene (1) in acetonitrile has been observed using 1H and 19F NMR spectroscopy.18

Potassium fluoride or cesium fluoride solubilized in toluene with 18-crown-6 induces alkyl- and aryl-group rearrangement on chloromethyl-substituted silanes.19

Oxygen Anions.

Acetate solubilized as the potassium salt in acetonitrile or benzene containing 18-crown-6 becomes sufficiently nucleophilic to react smoothly and quantitatively, even at room temperature, with a wide variety of organic substrates.20,21 Substitution reactions at primary, secondary, tertiary, and benzylic positions have been demonstrated.18 In certain cases, competing elimination processes are observed. Mixed anhydrides are formed in the reaction of the potassium or sodium salts of carboxylic acids with Ethyl Chloroformate, cyanuric chloride, or Benzyl Chloroformate in acetonitrile in the presence of 18-crown-6.22 Potassium phenylacetate has been reacted with a series of 2-bromo-substituted carbonyl compounds in the presence of 18-crown-6 to form aldehydo or keto esters which were subsequently cyclized to five-membered unsaturated lactones on further heating (eq 2).23

3-Bromoacetyl-7-methoxycoumarin is readily coupled with a wide variety of carboxylic acids in the presence of potassium bicarbonate and 18-crown-624 to form fluorescent derivatives. Reaction of alcohol mesylate with cesium acetate and 18-crown-6 in benzene is an effective method for the inversion of cyclopentyl and cyclohexyl alcohols.25

Reaction of 3-(bromomethyl)thiophene with the potassium salt of 4-cyano-4-hydroxybiphenyl in THF, in the presence of 18-crown-6, produces high yields of the substitution product.26

Potassium Superoxide, dissolved in benzene, THF, or DMF using 18-crown-6, reacts with stoichiometric quantities of primary and secondary alkyl bromides to produce dialkyl peroxides.27 The nucleophilic displacements by the superoxide radical anion and the intermediate alkyl peroxyanion on a chiral alkyl bromide ((R)-2-bromooctane) proceeds with inversion of configuration.26 The nucleophilic reaction of alkyl halides, methanesulfonates, and tosylates in Dimethyl Sulfoxide, DMF, or DME with 4 equiv of potassium superoxide in the presence of 18-crown-6 produces excellent yields of the corresponding alcohols (eq 3).28,29

When secondary halides were used, some elimination products accompanied the formation of the alcohol product. In general, substrate reactivity varied as follows: benzyl > primary > secondary > tertiary > aryl and I > Br > OTs > Cl. Reaction of the tosylate of (+)-(S)-2-octanol with superoxide produced (-)-(R)-2-octanol.28 The reaction of esters of carboxylic acids with approximately a threefold excess of potassium superoxide solubilized in benzene with 18-crown-6 produces, after acidic workup, the corresponding alcohols and carboxylic acids.30 Reaction of superoxide with the acetate ester of (-)-(R)-2-octanol gave only (-)-(R)-2-octanol, indicating that the reaction proceeds by means of an acyl-oxygen cleavage.29 Potassium superoxide dissolved in benzene with 18-crown-6 is an effective reagent for promoting the oxidative cleavage of a-keto, a-hydroxy, and a-halo ketones, esters, and carboxylic acids to carboxylic acids.31

18-Crown-6 enhances the rate of anionic oxy-Cope rearrangement by ion-pair dissociation.32

The reaction of ethyl tosylate and Ethyl Iodide with the sodium salt of Ethyl Acetoacetate in THF has been studied in the absence and presence of 18-crown-6. In the reaction with ethyl tosylate the presence of the crown increases the amount of oxygen alkylation. In contrast, the crown has little effect on the ratio of oxygen to carbon alkylation when ethyl iodide is used.33

An addition reaction of 3-benzyloxymethyl-3-methyloxetane with S-phenyl thioacetate in the presence of 18-crown-6/potassium phenoxide gave 3-benzyloxy-2-methyl-2-phenylthiomethylpropyl acetate in excellent yields.34

The dibenzyl ether of optically active diethyl tartrate has been prepared on a large scale using Sodium Hydride, Benzyl Bromide, Tetra-n-butylammonium Iodide, and a catalytic quantity of 18-crown-6.35

Carbon Anions.

Potassium Cyanide dissolved in acetonitrile using 18-crown-6 reacts with a variety of alkyl halides to produce the corresponding alkyl cyanides.36 As in the cases involving fluoride and acetate, some elimination processes accompanied substitution in certain cases. Under solid-liquid phase transfer catalytic conditions, primary alkyl chlorides react faster than bromides whereas the opposite is true for the corresponding secondary halides. Cyanotrimethylsilane has been synthesized from Chlorotrimethylsilane.37 cis-2-Chloro-4-methylcyclohexanone reacts with naked cyanide to exclusively produce the substitution product.11 Hydrocyanation of a,b-unsaturated nitriles and ketones with naked cyanide in the presence of Acetone Cyanohydrin has been reported (eq 4).38

Either 1,4-, 2,4-, or 1,5-hexadiene has been deprotonated with Cs 18-crown-6 solutions to produce hexadienyl anions.39

The isomerization of 2-methylbicyclo[2.2.1]hepta-2,5-diene to 5-methylenebicyclo[2.2.1]hept-2-ene using excess Potassium t-Butoxide in DMSO in the presence and in the absence of an equivalent concentration of 18-crown-6 has been investigated (eq 5).40 In the absence of crown, the order with respect to the base changed from zero order at high concentrations to first order at more dilute concentrations. In the presence of crown, the order with respect to base remained first order at all reported concentrations.

2,2,3-Triphenylpropylcesium rearranges in THF at 65 °C with 96% 1,2-migration of phenyl, whereas the corresponding lithium salt rearranges with at least 98% 1,2-migration of benzyl at 0 °C. The addition of 18-crown-6 as a ligand for the potassium and cesium salts significantly increases the extent of 1,2-benzyl migration.41

Treatment of trimethylsilyl trichloroacetate with a,a,a-trifluoroacetophenone in the presence of catalytic quantities of 18-crown-6 and Potassium Carbonate at 150 °C, followed by treatment with methanolic Potassium Hydroxide at 50 °C, produced excellent yields of Mosher's acid (a-methoxy-a-(trifluoromethyl)phenylacetic acid).42

18-Crown-6 is an effective catalyst in the dialkylation of o-nitrophenacyl derivatives.43

Nitrogen Anions.

N-Propargylpyrrole was prepared by the reaction of pyrrole with powdered potassium hydroxide in toluene, catalyzed by 18-crown-6.44

The reaction of naked nitrite with primary alkyl halides forms nitro compounds as the major product; the major byproducts are nitrite esters.23

Excellent yields of N-alkylation products were obtained in the reaction of dry alkali metal salts of 2-nitroimidazoles and methyl bromoacetate under homogeneous conditions at room temperature in the presence of 18-crown-6 in acetonitrile.45

Organic carbamates have been prepared in good yields from the reaction of primary amines, carbon dioxide, and an alkyl halide in the presence of 18-crown-6.46

Nitrogen Cations.

Photolysis of 1-aminopyridinium salts, 2-aminoisoquinolinium salts, and 1-aminoquinolinium salts is reported to give aniline or a mixture of 2-, 3-, and 4-toluidines in benzene-trifluoroacetic acid or in toluene-trifluoroacetic acid.47 An intermediate nitrenium ion is postulated. The presence of 18-crown-6 increases the yields of the above products.

Indazoles are produced in good yields from the reaction of o-methyl- and o-ethylbenzenediazonium tetrafluoroborates with two equivalents of potassium acetate in the presence of catalytic quantities of 18-crown-6 in ethanol-free chloroform.48

Other Anions.

Reaction of potassium dihydrogenphosphide with aromatic esters in the presence of 18-crown-6 produces potassium benzoylphosphide.49 Reaction of potassium dihydrogenphosphide with diethyl phthalate produces the potassium 18-crown-6 complex salt of the 2H-isophosphindoline-1,3-dione ion (2).50

Reductions.

Alkoxysulfonium salts dissolved in methylene chloride are smoothly reduced with Sodium Cyanoborohydride dissolved in methanol or ethanol in the presence of 18-crown-6.51 Even in the presence of aldehydes or ketones, only reduction of alkoxysulfonium salt was observed.

The titanium complex generated by the reaction of Dichlorobis(cyclopentadienyl)titanium with Sodium Borohydride promotes hydroboration of alkenes and alkynes in the presence of 18-crown-6.52,53

Radical anions of mesitylene, toluene, and benzene are formed in the reaction with alkali metals and 18-crown-6.54 The alkyl-oxygen bond of oxetane is cleaved with K-/K+ and Na-/K+ complexes in which the potassium cation has been complexed with 18-crown-6 to form an organometallic alkoxide.55

Hydrosilylation of carbonyl groups with Dimethyl(phenyl)silane proceeds in methylene chloride, benzene, or THF, in the presence of catalytic quantities of cesium, rubidium, or potassium fluoride/18-crown-6.56

Oxidations.

The homogeneous photosensitization of oxygen by solubilizing the anionic dyes Rose Bengal and Eosin Y in methylene chloride and Carbon Disulfide using 18-crown-6 has been reported. The presence of singlet Oxygen was demonstrated by trapping with anthracene and tetramethylethylene.57

The carbanions from tri- and diarylmethanes are generated and oxidized to triaryl carbinols and diaryl ketones, respectively, using potassium hydroxide/DME/18-crown-6 in the presence of oxygen.58

Chromium(VI) Oxide, in the presence of 18-crown-6 catalyst in methylene chloride, is an efficient oxidizing system for the chemoselective oxidation of thiols to disulfides.59

Eliminations.

The generation of free carbenes was demonstrated in the reaction of Potassium t-Butoxide with Chloroform, a-bromo-a-fluorotoluene, and a,a-dichlorodimethyl sulfide in the presence of 18-crown-6 from competitive reactivities toward alkenes.60,61 Diazomethane was synthesized in 48% yield from the reaction of Hydrazine hydrate, chloroform, and potassium hydroxide in ether in the presence of catalytic quantities of 18-crown-6.62

Reaction of exo-2-norbornyl-exo-3d tosylate with the sodium salt of 2-cyclohexylcyclohexanol in triglyme produces norbornene containing no deuterium. This represents an exclusive syn elimination process.63 In the presence of 18-crown-6, 27% of the product contains deuterium, thus indicating some anti elimination.63 The results were interperted in terms of the effects of crown on base association and ion-pairing.

Polymerization.

In the polymerization of methacrylic esters and hindered alkyl acrylates, the presence of 18-crown-6 produces living polymers in apolar solvents, such as toluene, and at temperatures as high as 0 °C.64 The polymerization of b-lactones proceeds smoothly in the presence of Potassium Naphthalenide only after the addition of a cation complexing ligand such as 18-crown-6.65 The anionic polymerization of Propylene Oxide and ethylene oxide is catalyzed by the potassium salt of methoxypropanol in the presence of 18-crown-6.66 The monomer 5-(bromomethyl)-1,3-dihydroxybenzene undergoes self-condensation in the presence of potassium carbonate and 18-crown-6 to give hyperbranched polyethers.67 The synthesis of soluble, substituted silane high polymers by Wurtz coupling techniques is facilitated by the presence of 18-crown-6.68 Interfacial polycondensation to produce poly(arylcarboxylate)s,69 polyphosphates,70 and polyphosphonates46 has been studied in the presence of 18-crown-6. Polycondensations of 4-bromomethylbenzyl bromide were carried out with 4,4-oxydibenzenesulfinate in the presence of 18-crown-6.71

Reactions on Polymers.

18-Crown-6 facilitates the alkaline hydrolysis of nitrile groups in acrylonitrile-divinylbenzene copolymer.72 Starting from linear polycarbonate, carbonate-formal copolymers were prepared by reaction with Dibromomethane, potassium hydroxide, and 18-crown-6.73 Polystyrene has been successfully grafted onto carbon whiskers by anionic graft polymerization of styrene in which OLi groups on the surface of the carbon whiskers are activated by 18-crown-6.74 The reaction of chloromethylated poly(styrene-co-divinylbenzene) with potassium superoxide in the presence of 18-crown-6 has been reported.75

Related Reagents.

Dibenzo-18-crown-6; Dicyclohexano-18-crown-6; Potassium t-Butoxide-18-Crown-6; Potassium Carbonate-18-Crown-6; Potassium Hydroxide-18-Crown-6.


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Charles, L. Liotta & Joachim Berkner

Georgia Institute of Technology, Atlanta, GA, USA



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