Structure-cation complexation relationships for ortho-, meta-, and para-substituted bis(oxymethylcrown)benzenes and α , α '-xylenes

New bis(crown ether) compounds are synthesized by attaching two (hydroxymethyl)crown ether units to a benzene or α , α '-xylene framework. Bis(15-crown-5) polyether substitution patterns are varied from ortho to meta to para. ortho -Bis(18-crown-6) polyethers are prepared together with mono(crown ether) analogs, as well as ortho -bis(12-crown-4) polyethers. Complexation abilities of these compounds for alkali metal cations are evaluated by picrate extraction allowing the influence of structural modifications in the ligands on extraction constants (K ex ) and association constants (K a ) for alkali metal cations to be assessed.


Introduction
2][3][4][5] This led to the synthesis of new compounds in which two or more crown ether units were covalently linked in a fashion to promote formation of intramolecular 2:1 (crown ether:cation) complexes. 6[9][10][11][12][13] We now report the results of a systematic study of structural variations in bis(crown ethers) formed by attaching two (hydroxymethyl)crown ether units to a benzene or α,α'-xylene framework.The influence of these structural variations (crown ether ring size and length of the spacer between the crown ether ring and the central benzene ring) upon alkali metal cation complexation are assessed by picrate extraction.α,α'-Bis-[(oxymethyl)crown] xylenes 4-6 and 9-11 were synthesized by reaction of the appropriate (hydroxymethyl)crown ether with NaH in THF and then with the appropriate α,α'dibromoxylene.Refluxing the mixture overnight and workup with purification of the crude product by column chromatography produced these polyether ligands as oils in 50-77% yields.
For bis(crown ethers) 1-3 and 4-6, the systematic structural variation is changing the crown ether ring size from 12-crown-4 to 15-crown-5 to 18-crown-6.For the two series of bis(crown ethers) 2, 7, 8 and 5, 9, 10, there is a common 15-crown-5 ring size and the attachment of the two crown ether-containing substituents to the central benzene unit is varied from ortho to meta to para.The series of bis(crown ethers) 1-3, 7, 8 differs from the series 4-6, 9, 11 in the former has a -CH 2 O-linkage between the crown ether ring and benzene ring and for the latter this linkage is -CH 2 OCH 2 -.For meta-bis (15-crown-5) ethers 9 and 11, the hydrogen on the benzene ring between the two crown ether-containing substituents in the former is replaced by a methoxy group in the latter.
The alkali metal ion complexing properties of bis(crown ether) ligands 1-11 and their mono(crown ether) analogs 12 and 13 were evaluated by alkali metal picrate extractions from aqueous solutions into deuteriochloroform.Extraction constants (K ex ) 14 and association constants (K a ) 15 were calculated by reported procedures.The stoichiometry of each extraction complex was ascertained from the position of the absorption maximum for the picrate anion in the organic phase after dilution with THF. 5 A maximum in the range of 375-385 nm indicates a separated ion pair and is consistent with formation of a sandwich complex involving two crown ether units and one metal ion.A maximum in the range of 355-365 nm reveals a tight ion pair and association of the alkali metal cation with a single polyether ring.Hereafter, we will refer to the former as a 2:1 complex [even though both crown ether rings are provided by a bis(crown ether) ligand] and the former as a 1:1 complex.

Bis(12-crown-4) hosts 1 and 4
Picrate extraction data and association constants (K a ) for complexation of alkali metal picrates by bis(crown ethers) 1 and 4, which each have two 12-crown-4 rings, are presented in Table 1.][18] Although at least one X-ray crystal structure has appeared showing Li + in a 12-crown-4 sandwich complex, 19 this is probably a rare occurrence, especially in solution.The λ max values observed for extractions of lithium picrate by bis(crown ethers) 1 and 4 indicate separated ion pairs.However, it is postulated that this is the result of water in the Li + solvation sphere of the extraction complex, rather than formation of a sandwich complex.
Although the association constants for all of the alkali metal cations are small, both bis(12crown-4) ligands 1 and 4 exhibit their greatest extraction capacity for Na + .The λ max values for sodium picrate extraction are intermediate between those for tight and separated ion pairs indicating that the extraction complexes are a mixture of Na + associated with one and both crown ether rings in the bis(crown ether) host.The association constant for complexation of sodium picrate is higher for 4, which has a longer spacer between the polyether ring and the central benzene ring, than for 1.The λ max values for complexes formed in potassium, rubidium, and cesium picrate extractions are consistent with 2:1 complexes.

Bis(15-crown-5) hosts
The influence of two different structural modifications were probed with bis(15-crown-5) ethers: i) attachment of the two crown ether-containing substituents ortho, meta, and para on the central benzene ring; and, ii) changing the length of the spacer between the crown ether unit and the central benzene ring.

Bis(oxymethyl-15-crown-5)benzenes 2, 7, and 8
Picrate extraction data and association constants (K a ) for complexation of alkali metal picrates by bis(crown ethers) 2, 7, and 8, which each have two -OCH 2 (15-crown-5) substituents, are presented in Table 2. Extractions of Li + and Cs + were uniformly inefficient throughout the series.Association constants for complexation of sodium picrate by 2, 7, and 8 are high and show little variation as the attachment of the crown ether-containing substitutents is varied from ortho to meta to para.The λ max values are consistent with 1:1 complexation of Na + .On the other hand, the λ max values reveal 2:1 complexation with the ortho-substituted ligand 2 and K + , as well as Rb + and Cs + .The association constants for complexation of alkali metal picrates by ligand 2 decrease in the order of K + >Na + >Rb + >Cs + >Li + .The meta-substituted isomer 7 formed a precipitate when the deuteriochloroform solution obtained by extraction of the aqueous potassium picrate solution was diluted with THF, rendering determination of the stoichiometry by UV-visible absorbance impossible (see Experimental Section).However, the 1:1 complex stoichiometry evident for K + with the para-substituted isomer 8 and the similarity of association constants for complexation of K + with 7 and 8 strongly suggests formation of a 1:1 complex for 7 with K + as well.The λ max values for complexes of Rb + and Cs + with 7 and 8 are also consistent with 1:1 complexation.
Association constants for complexation of alkali metal picrates by the metaand parasubstituted isomers 7 and 8, respectively, decrease in the order Na + >K + >Rb + >Cs + >Li + , which is a reversal of the relative positions for Na + and K + in the ordering observed for the orthosubstituted isomer 2. The enhanced complexation of K + by 2 is clearly evident from the graphical presentation of the association constant data for isomers 2, 7, and 8 in Figure 1.

α,α'-Bis(oxymethyl-15-crown-5)xylenes 5 and 9-11
Picrate extraction data and association constants (K a ) for complexation of alkali metal picrates by bis(crown ethers) 5, 9, and 10, which each have two -CH 2 OCH 2 (15-crown-5) substituents, are presented in Table 3.For 5, 9, and 10, the structural variation is attachment of the two crown ether-containing substituents ortho, meta, and para, respectively on the central benzene ring.In almost every case, association constants for complexation of the alkali metal picrates were increased by lengthening of the spacer between the crown ether unit and central benzene ring in bis(15-crown-5) analogues 2, 7, and 8.Only the association constants of 5 with Cs + and 10 with Rb + showed decreases compared with 7 and 8.
Extraction efficiencies of these hosts for Li + were again uniformly low.Association constants for Na + remain constant as the attachment sites for the two crown ether-containing substituents are varied from ortho to meta to para.Once again the λ max values show that the ortho isomer (5) forms 2:1 complexes with K + and Rb + .The extraction complex for Cs + and 5 appears to have mixed stoichiometry.
Although some propensity for complexation of the larger metal ions is lost in going from ortho-isomer 5 to meta-isomer 9, the λ max values reveal that the latter continues to form 2:1 complexes with K + and Rb + .The para-isomer 10 does not form 2:1 complexes with any of the alkali metal cations.Differences in the nature of K + and Rb + complexation by 5 and 9 versus 10 is responsible for the markedly enhanced affinities of 5 and 9 for these alkali metal cations, especially for Rb + (see Figure 2).Small, but steady, increases in association constants for Cs + complexation in going from 5 to 9 to 10 may be due to easier formation of intermolecular complexes of the 2:1 type or could reflect enhanced interaction of this soft cation with the πelectron cloud of the benzene ring during complexation. 20However, preliminary 1 H NMR studies of 10 in d 6 -acetone showed no downfield shift of the aromatic protons upon addition of cesium nitrate to the sample, indicating little or no π-cloud interaction.Cesium picrate extractions were conducted using a different concentration.
For the bis(18-crown-6) ligands 3 and 6, λ max values for all of the alkali metal picrates except Li + are consistent with 1:1 complexes.In agreement, K + , which provides the best match with the cavity size of a single 18-crown-6 unit, has the largest association constant.Association constants for complexation of alkali metal picrates decrease in the order K + >Rb + >Cs + >Na + >Li + .Although the λ max values for Li + might suggest 2:1 complexes, they are attributed instead to the ability of Li + to carry waters of solvation into its complexes with large ring crown ethers. 21

Comparison of bis(18-crown-6) hosts 3 and 6 with mono(18-crown-6) hosts 12 and 13
In the extraction studies of K + with bis(18-crown-6) compounds 3 and 6, the association constants were so high that it was necessary to conduct separate extractions at a host:guest ratio of 1:2 (ligand:alkali metal picrate).Extraction data and association constants for bis(18-crown-6) ligands 3 and 6 determined under these conditions are compared with those for mono(18-crown-6) model compounds 12 and 13 obtained with the customary 1:1 host:guest ratio are presented in Table 5.The differing ratios correct for the fact that each bis(crown ether) ligand provides two 18-crown-6 units, while each mono(crown ether) molecule has a single 18-crown-6 ring.
Comparison of the data for bis(crown ether) 3 with mono(crown ether) 12 and of bis(crown ether) 6 with mono(crown ether) 13 reveals no substantial differences between the extraction data and association constants obtained under these conditions.This is consistent with formation of only 1:1 complexes (one crown ether unit per metal ion) and is supported by the λ max values for the four ligands.

Summary
The new biscrown ethers 1-10 provide a series with systematic structural variations of the ring size, the positioning of the two crown ether rings on a central benzene unit and the length of the tether that connects each crown ether unit to the benzene ring.Alkali metal picrate extraction results reveal that these structural variations affect the efficiency with which a particular metal ion is extracted, as well as its interaction with one or both crown ether rings.
In 1 and 4, the two 12-crown-4 rings are attached ortho on the benzene ring by -OCH 2 -and -CH 2 OCH 2 -units, respectively.Compared with the other biscrown ether compounds, 1 and 4 are only weak extractants for alkali metal cations.Both ligands give strongest complexation of Na + with formation of mixed complexes in which the metal ion interacts with one and both polyether rings.For K + and Rb + , both crown ether units interact with the complexed metal ion.
The most complete structural effect study includes the five bis(15-crown-5) compounds 2, 5, and 7-9.In the alkali metal picrate extractions, all of these ligands are weak extractants of Li + and Cs + .For 2, 7, and 8, the two crown ether rings are positioned ortho, meta and para, respectively, with -OCH s -tethers between the 15-crown-5 rings and the central benzene ring.The association constant orders are K + > Na + > Rb + for 2 and Na + > K + > Rb + for 7 and 8.This differing ordering for ortho-substituted ligand 2 results from interaction of K + with both crown ether rings; whereas the complexed metal ion interacts with only one cyclic polyether unit in 7 and 8.With alteration of the tether to -CH 2 OCH 2 -, the extraction selectivity is K + , Na + > Rb + for 5 and 9, but Na + > K + > Rb + for 10 with K + complexed by two crown ether rings in 5 and 9, but only one in 10.For the two ortho-substituted bis(18-crown-6) compounds 3 and 6, the stability constant order is K + > Rb + > Na + > Cs + > Li + and only interactions of the complexed metal ion with a single crown ether unit are evident.

Experimental Section
General Procedures.IR spectra were obtained on neat samples with a Nicolet MX-S spectrometer and are recorded in wavenumbers. 1 H NMR spectra were recorded with a Varian EM 360 spectrometer in CDCl 3 and chemical shifts are reported in parts per million (δ) downfield from TMS. UV-visible spectra were recorded with a Perkin-Elmer Lambda 5 spectrophotometer.Elemental analyses were performed by Galbraith Laboratories, Inc. of Knoxville, Tennessee.Unless specified otherwise, reagent-grade reactants and solvents were obtained from commercial suppliers and were used as received.THF was purified by distillation from LiAlH 4 under nitrogen.3][24][25] Ligand 13 was prepared by a reported method. 23The 2,6-bis(bromomethyl)anisole was obtained from 2,6-dimethylanisole by bromination with N-bromosuccinimide.

2-Methoxy-1,3-bis-(α,α'-oxymethyl-15-crown-5)-meta-xylene
Procedure for picrate extractions.Except where noted (Table II), extractions of alkali metal picrates with bis(crown ether) hosts were performed by placing 0.50 mL of a 15 mM solution of the metal picrate in deionized water and 0.50 mL of a 15 mM solution of the bis(crown ether) in deuteriochloroform into a 15-mL centrifuge tube and mixing the solutions on a vortex mixer for 60 sec.Five samples were prepared for each picrate extraction experiment.The tubes were centrifuged for 10 min and then allowed to stand for 10 min to assure complete separation of the layers.Aliquots were taken from each phase of the sample in the tube and the concentration of metal picrate in each phase was determined by UV-visible absorbance scanning from 550 nm to 320 nm.In some cases, the organic phase concentration was determined by difference from the aqueous phase readings before and after extraction because of turbidity or formation of complexes insoluble in THF.The extraction constants (K ex ) 14 and association constants (K a ) 15 were calculated according to previously developed methods.Standard deviations from the analysis of the five samples were less than 10% of the K ex and K a values.All extractions of cesium involved 5 mM cesium picrate and 15 mM bis(crown ether) due to the lower solubility of cesium picrate.

Table 1 .
Alkali metal picrate extraction from aqueous solution into deuteriochloroform by bis(12-crown-4) ligands 1 and 4 a Cesium picrate extractions were conducted using a different concentration.b Not detected.

Table 3 .
Alkali metal picrate extraction from aqueous solution into deuteriochloroform by bis(15-crown-5) ligands 5, 9, 10 and 11 a Cesium picrate extractions were conducted using a different concentration.b Calculated from aqueous phase absorbance readings (see Experimental Section).

Table 3 .
From the λ max values for alkali metal picrate extraction by 11, only 1:1 complexation is evident.In agreement, Na + , which provides the best match with the cavity size of a single 15crown-5 unit, has the largest association constant.Association constants for complexation of alkali metal picrates decrease in the order Na + >K + >Li + ,Rb + ,Cs + .Bis