Sterically congested, geminal aryl-substituted, proton-ionizable sym -dibenzo-16-crown-5 lariat ethers: synthesis and alkali metal cation extraction

Three series of proton-ionizable sym -dibenzo-16-crown-5 ethers with sterically demanding 1-naphthyl, 2-naphthyl, and 9-phenanthryl geminal groups are synthesized and characterized. Variation of the proton-ionizable group includes oxyacetic acid and N -(X)sulfonyl oxyacetamide units with X = Me, Ph, C 6 H 4 -4-NO 2 , and CF 3 . For the latter series, variation of X provides 'tunable' acidity of the ligand. The metal ion-complexing properties of the proton-ionizable sym - (aryl)dibenzo-16-crown-5 compounds are probed by competitive solvent extraction of alkali metal cations from aqueous solutions into chloroform.


Introduction
Crown ethers, macrocyclic polyethers with a hydrophobic ring of ethylenic units surrounding a hydrophilic cavity of ether oxygen atoms, are exceptionally versatile and powerful in selectively binding a range of metal ion species. 1-2 Attachment of one or more side arms onto a crown ether ring produces a lariat ether. 3 This may enhance metal ion binding strength and selectivity over monocyclic crown ethers by providing donor sites in addition to those of the macroring resulting in three-dimensional complexation, thereby mimicking the dynamic complexation processes exhibited by natural macrocyclic ionophores. 3 However, such complexing agents may not be effective in practical extractions of metal ions due to the low distribution coefficients of common counteranions, such as chloride, nitrate, and sulfate between an aqueous phase and a contacting organic phase. 4 This problem can be overcome by attaching a proton-ionizable side arm to the crown ether ring so that the ligand provides not only a polyether binding site for metal ion complexation, but also the requisite anion for formation of an electroneutral extraction complex. An ionizable group on the side arm eliminates the need to transfer one or more aqueous phase anions into the organic phase by operating in a cation-exchange mode with the metal ion. Following the extraction step, shaking of the separated organic phase with aqueous acid strips the extracted metal ions into a new aqueous phase and regenerates the neutral form of the extractant. [4][5] During a metal ion separation process, the presence of lipophilic groups on the crown ether ring is important in reducing loss of the macrocyclic ligand from an organic phase into a contacting aqueous phase. 6 The dibenzo-16-crown-5 ring system provides a convenient scaffold for investigating the influence of structural variation within lariat ethers upon their selectivity and efficiency in metal ion complexation processes due to its synthetic accessibility with pendant groups attached to the central carbon of the three-carbon bridge. [7][8] In earlier studies, we found that the introduction of a lipophilic decyl group geminal to the functional side arm in symdibenzo-16-crown-5 oxyacetic acid ( Figure 1) increased the Na + selectivity by preorganization of the binding site in which the alkyl group oriented the oxyacetic acid side arm over the polyether cavity. Various alkyl groups have been attached geminal to the proton-ionizable side arm in symdibenzo-16-crown-5 ethers to form effective and selective extractants for alkali metal cations. [5][6] In comparison, analogues with more sterically demanding geminal aryl groups have received very little attention. We now report the synthesis of three series of proton-ionizable sym-dibenzo-16-crown-5 ethers with geminal 1-naphthyl, 2-naphthyl, and 9-phenanthryl groups ( Figure 2  BrCH2CO2H, THF, rt; d) NaH, BrCH2CO2Me, THF, rt; e) i) 10% aq. NaOH, THF, rt; ii) 6 N HCl (aq); f) (COCl)2, C6H6, rt; g) NaH, NH2SO2X, THF, rt.
Preparation of sym-(keto)dibenzo-16-crown-5 (2) was accomplished in improved yield by the Swern oxidation of sym-(hydroxy)dibenzo-16-crown-5 (1). The lariat ether alcohols 3 and 4 were synthesized by the addition of 1-naphthyl-and 2-naphthylmagnesium bromides, respectively, to ketone 2. The Grignard reagents were formed by addition of a solution of the aryl bromide in THF to dry magnesium turnings. The mixture was heated to initiate the reaction, then stirred at room temperature until a colored solution was observed. Tertiary alcohols 3 and 4 were obtained in 95 and 90% yields, respectively.
Deprotonation of alcohol 4 with NaH in THF followed by addition of dry bromoacetic acid gave sym-(2-naphthyl)dibenzo-16-crown-5-oxyacetic acid 7 in 82% yield. However, analogous reaction of alcohol 3 gave only a low yield of lariat ether carboxylic acid 6. In an alternate route, a solution of methyl bromoacetate in THF was added to the deprotonated alcohol 3 in THF to produce methyl sym-(1-naphthyl)dibenzo-16-crown-5-oxyacetate (5) in 79% yield. Subsequent stirring of the ester with aqueous 10% NaOH and THF followed by protonation of the resultant lariat ether carboxylate gave 6 in 85% yield.
Synthesis of N-(X)sulfonyl sym-(aryl)dibenzo-16-crown-5-oxyacetamides 10-17 from the corresponding carboxylic acids 6 and 7 was accomplished by a two-step procedure. First, the carboxylic acid was reacted with oxalyl chloride in benzene to give the corresponding acid chloride. Formation of the acid chloride was verified by IR spectroscopy with the appearance of the strong carbonyl group absorption near 1810 cm -1 and the disappearance of the carbonyl group absorption around 1730 cm -1 . [11][12] The crude acid chloride was reacted with the corresponding sodium sulfonamide anions in THF to afford proton-ionizable sym-(aryl)dibenzo-16-crown-5 ethers 10-17 in 37-75% yields.
The synthetic route to the new proton-ionizable sym-(9-phenanthryl)dibenzo-16-crown-5 ethers is presented in Scheme 2. To initiate formation of the Grignard reagent from 9phenanthryl bromide and Mg in THF, a crystal of iodine was needed. A solution of ketone 2 in THF was added to the Grignard reagent and the mixture was stirred overnight. After workup, lariat ether tertiary alcohol 18 was obtained in 82% yield. Attempted reaction of alcohol 18 with NaH and bromoacetic acid in THF was unsuccessful. In an alternative synthetic route, the alcohol precursor was deprotonated by NaH in THF and ethyl bromoacetate was added. After reaction and workup, the product was found to be the lariat ether carboxylate 19 instead of the anticipated ethyl ester. This was unusual since similar reactions reported in literature always gave esters. [13][14] Protonation of the lariat ether carboxylate gave the target lariat ether carboxylic acid 19 in 91% yield. As described earlier, the carboxylic acid 19 was converted into the corresponding acid chloride 20 by reaction with oxalyl chloride in benzene followed by reaction of the crude acid chloride with the appropriate sodium sulfonamide in THF to produce the proton-ionizable sym-(9-phenanthryl)dibenzo-16-crown-5 ethers 21-24 in 70-94% yields.
For each of the three series of compounds with N-(X)sulfonyl oxyacetamide functional side arms, the carbonyl group IR absorption increased in wavenumbers as the electron-withdrawing ability of X was enhanced in the order Me ≤ Ph < C6H4-4-NO2 < CF3 (Table 1). Also in the 1 H NMR spectra for N-(X)sulfonyl oxyacetamides 10-17 and 21-24, the NH peaks for each of the three series shifted further downfield as the electron-withdrawing ability of X increased in the order Me < Ph < C6H4-4-NO2 < CF3 (Table 2).  1 H NMR spectroscopy provides qualitative information about the flexibility of the crown ether ring. 5,9 Lariat ethers with a three-carbon bridge have two limiting conformations in solution, as illustrated in Figure 3. The two methylene protons in the three-carbon bridge are diastereotopic. The rate of conformational inversion can be estimated from the spin pattern of the geminal protons. An AB pattern results from rapid conformational inversion, which indicates a flexible ring structure. Interesting differences are observed in the 1 H NMR spectra of the N-(X)sulfonyl sym-(aryl)dibenzo-16-crown-5-oxyacetamides 10-17 and 21-24 in CDCl3. AB patterns were found when the aryl group was 1-naphthyl and 9-phenanthryl; whereas AX patterns were noted when the aryl group was 2-naphthyl. By this measure, the crown ether rings in the proton-ionizable sym-(2-naphthyl)dibenzo-16-crown-5 lariat ethers 6 and 10-13 in solution are judged be more rigid. Of the lariat ether carboxylic acids, 7 with a 2-naphthyl group was insoluble in CDCl3. In d6-DMSO, an AB pattern was observed. In CDCl3, 6 with a 1-naphthyl group exhibited an AB pattern and 19 with a 9-phenanthryl group showed an A2 singlet for the geminal protons on the three-carbon bridge.

Competitive solvent extraction of alkali metal ions
The metal ion-complexing properties of proton-ionizable lariat ethers 6, 7, 10-17, 19, and 21-24 were evaluated by competitive solvent extraction of alkali metal cations from aqueous solutions into chloroform. Aqueous solutions of Li + , Na + , K + , Rb + , and Cs + (10 mM in each) with varying pH were extracted with equal volumes of chloroform containing 1.0 mM proton-ionizable lariat ether. After separation of the chloroform layer, it was stripped with 0.1 M aqueous HCl. Alkali metal cation concentrations in the strippants were determined by ion chromatography. Extraction results for the three sym-(aryl)dibenzo-16-crown-5-oxyacetic acids 6, 7, and 19 with geminal 1-naphthyl, 2-naphthyl, and 9-phenanthryl groups, respectively, are presented in Figure 4. As is readily evident, all three ligands are highly selective extractants for Na + . The extraction selectivity order is Na + >> K + > Li + , Rb + , Cs + with barely detectable or negligible levels of the last three alkali metal cations. The maximal Na + /K + selectivities for 6, 7, and 19 exceeded 100, which is the precision of the alkali metal cation analysis. In comparison, a Na + /K + ratio of 27 was reported for competitive alkali metal cation extraction by sym-(decyl)dibenzo-16crown-5-oxyacetic acid. 6 Thus replacement of the geminal linear alkyl group in the lariat ether carboxylic acids with geminal 1-naphthyl, 2-naphthyl, and 9-phenanthryl units produces a marked enhancement in the selectivity for Na + extraction. Alkali metal cation loading is nearly quantitative for formation of 1:1 ionized lariat ether-metal ion extraction complexes. Such high extraction selectivity for Na + strongly suggests simultaneous metal ion complexation by the polyether oxygens and the oxyacetic acid side arm. 6,9 A qualitative measure of acidity for proton-ionizable ligands is pH0.5, the aqueous phase pH at which half of the maximal metal ion loading is reached. 15 For lariat ether carboxylic acids 6, 7, and 19, the same pH0.5 value of 7.0 was observed. Thus structural variation of the geminal aryl group from 1-naphthyl to 2-naphthyl to 9-phenanthryl in the sym-(aryl)dibenzo-16-crown-5oxyacetic acid extractants did not influence the ligand acidity.
Magnitudes of the pH0.5 values for a given X when the geminal group is 9-phenanthryl are more similar to those when the geminal group is 1-naphthyl than 2-naphthyl.

Conclusions
Three series of proton-ionizable sym-(aryl)dibenzo-16-crown-5 ligands with systematic structural variations in the geminal aryl group and the functional side arm have been synthesized. The aryl group identity was varied to include 1-naphthyl, 2-naphthyl, and 9-phenanthryl. Functional side arms employed were oxyacetic acid and N-(X)sulfonyl oxyacetamide with changes of X from Me and Ph to C6H4-4-NO2 to CF3 to 'tune' the acidity of the proton-ionizable side arm. The metal cation complexing abilities of the 15 new proton-ionizable lariat ethers were assessed by competitive solvent extractions of five alkali metal cation species from aqueous solution into chloroform. All 15 compounds exhibited high Na + extraction selectivity consistent with threedimensional complexation of the metal ion by the polyether oxygens and the ionized side arm. For the three sym-(aryl)dibenzo-16-crown-5-oxyacetic acids, the extraction selectivity order was Na + >> K + > Li + , Rb + , Cs + with Na + /K + selectivity ratios exceeding 100, the upper limit for the recrystallized from THF-hexanes (3:1) to give 3.92 g (76%) of white needles with mp 141-143 o C (lit 8 mp 138-139 o C).

General procedure for the synthesis of sym-(aryl)(hydroxy)dibenzo-16-crown-5 compounds 3 and 4
Oven-dried magnesium turnings (1.06 g, 43.6 mmol) in THF (20 mL) were added to a 3-necked flask under nitrogen. A solution of the appropriate aryl bromide in THF (20 mL) was added dropwise via an addition funnel over a 0.5-h period. The reaction was initiated by heating followed by stirring for 2 h at room temperature. Once the Grignard reagent had formed (indicated by a gray/green solution and the disappearance of Mg), a solution of lariat ether ketone 2 (5.00 g, 14.5 mmol) in THF (50 mL) was added dropwise over a 30-min period. The mixture was stirred overnight and the reaction was quenched by addition of 5% aq NH4Cl (75 mL). The THF was evaporated in vacuo and the residue was extracted with CH2C12 (2×75 mL). The combined CH2C12 layers were dried over MgSO4 and evaporated in vacuo to give a white solid. The residue was purified by column chromatography or recrystallization.

sym-(Hydroxy)(9-phenanthryl)dibenzo-16-crown-5 (18).
Dry magnesium turnings (1.64 g, 67.5 mmol) were placed in an oven-dried, 3-necked flask equipped with a dropping funnel and a condenser under nitrogen. THF (10 mL) and a crystal of iodine were added to the flask. A solution of 9-bromophenanthrene (15.42 g, 60 mmol) in THF (70 mL) was added over a 30-min period. The mixture was heated to initiate the reaction and then the mixture was stirred at room temperature. The reaction was completed when the color of the mixture turned yellow-brown (about 3 h). A solution of 2 (5.16 g, 15 mmol) in THF (100 mL) was added over a 2-h period. The mixture was stirred overnight. After cooling to 0 ºC, 5% aq NH4Cl (30 mL) was added to the flask dropwise. After stirring for 10 h, the white solid was filtered. For the filtrate, the THF was evaporated in vacuo and the aqueous solution was extracted with CH2Cl2 (2  50 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo. The filtered solid and the additional solid recovered from the filtrate were combined and recrystallized from hexanes-THF (2:1) to obtain 6.40 g (82%) of white solid with mp 97-98 o C. νmax (film)/cm - Methyl sym-(1-naphthyl)dibenzo-16-crown-5-oxyacetate (5). NaH (0.39 g, 16.9 mmol) and THF (20 mL) were added to a 3-necked flask. The mixture was stirred under nitrogen for 30 min and a solution of lariat ether alcohol 3 (2.00 g, 4.33 mmol) dissolved in THF (20 mL) was added dropwise over a 1-h period. After stirring for 1 h, a solution of methyl bromoacetate (0.80 g, 8.46 mmol) in THF (50 mL) was added dropwise over a 3-4-h period. The reaction mixture was stirred for an additional 10 h and then quenched by cooling to 0 o C and adding water (20 mL). The THF was evaporated in vacuo and water (10 mL) was added to the mixture. After extraction with CH2C12 (3 × 25 mL), the combined organic layers were dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel with hexanes-Et2O (1:1) then EtOAc as eluents to give 1.