Synthesis of novel cage-annnulated fluoromacrocycles

Two new cage functionalized, partially fluorinated crown ethers ( 7 and 9 ) have been synthesized. The structure of 7 has been established unequivocally via application of X-ray crystallographic methods.


Introduction
Pedersen's 1 early investigations of the host-guest chemistry of macrocyclic crown ethers has led to an explosion of interest in their use as host systems for the study of molecular recognition and inclusion phenomena.Numerous applications of crown ethers arise from their ability to enter into selective complexation with alkali metal cations and to transport these species selectively across liquid membranes. 2,3ore recently, the introduction of covalently bonded fluorine into crown ethers and cryptands has attracted considerable interest worldwide.The existence of electrostatic interactions of the type C-F•••M + have been demonstrated both in the solid state (X-ray structure studies) 4 and in solution (NMR spectroscopic studies). 5These experimental observations are supported by the results of theoretical calculations. 6The high electronegativity and hardness of fluorine 7 render covalently bonded fluorine (C-F) suitable as an electron-pair donor for complexation with hard acceptors, e.g., alkali metal (Group I) and alkaline earth (Group II) metal cations, respectively. 8itherto, we have demonstrated that cage-annulated crown ethers, 9 cryptands, 10 molecular clefts, 11 and molecular boxes, 12 constitute a new class of host systems for the study of host-guest interactions (i.e., molecular recognition and inclusion phenomena).Recently, we have undertaken the synthesis of some fluorine-containing analogs of these systems.In the present study, we report the synthesis of a fluorinated podand, 5 (Scheme 1), which subsequently has been converted into two cage-annulated, fluorine-containing crown ethers, i.e., 7 and 9 (Scheme 2).

Scheme 1 Scheme 2 X-Ray crystal structure of 7
The structure of crown ether 7 was established unequivocally via application of X-ray crystallographic methods.A structure drawing of 7 is shown in Figure 1.Inspection pf the structure drawing reveals that incorporation of a 3,5-difunctionalized oxahexacyclic cage moiety and a 2,6-disubstituted pyridine ring into the macrocyclic backbone confers a measure of rigidity upon the crown ether and thereby provides a degree of preorganization to the resulting cavity.In addition, it should be noted that the cage moiety serves as a lipophilic component, thereby reducing the solubility of cage containing crown ethers in water and assisting in its recovery via extraction into a nonpolar medium.

Results of alkali metal picrate extraction experiments
Alkali metal picrate extraction experiments were performed by using a previously published procedure 16 with 7 and 9 as hosts in a chloroform-water binary solvent system.The results thereby obtained, shown in Table 1, are compared with the corresponding results obtained for two previously studied model systems, i.e., 18-crown-6 and a cage annulated host, 10 17 , that serves as a structural analog of 7. The data in Table 1 indicate that 7, 9, and 10 are inefficient alkali metal cation complexants relative to 18-crown-6.

Table 1. Alkali metal picrate extraction data
a Averages and standard deviations calculated for data obtained from three independent extraction experiments; see reference 17. b Averages and standard deviations calculated for data obtained from six independent extraction experiments.c BLD = Below limit of detection.
Other investigators 5 have observed characteristic changes in 1 H, 13 C, and 19 F NMR spectra of complexes between fluorinated hosts and metal cation guests that provide clear evidence for the importance of C-F•••M + interactions in the systems that they studied.However, it should be noted that many of the reported examples involve fluorinated cages that contain a highly preorganized, nearly cyclic array of several C-F bonds that are capable of binding tightly to a metal cation guest via multiple C-F•••M + interactions.The lack of similar preorganization of the C-F bonds present in cage-annulated crown ethers 7 and 9 relative, e.g., to the types of fluorinated cage hosts studied by Takemura and coworkers 5b,5c may account for the relatively poor efficiencies that we observed when we attempted to employ 7 and 9 as alkali metal cation complexants and/or extractants.

Summary and Conclusions
Two novel cage-annulated, fluorine-containing crown ethers, i.e., 7 and 9, have been prepared via an efficient synthesis that employs commercially available 2,2,3,3-tetrafluorobutane-1,4-diol.The structure of one of these crown ethers, i.e., 7, has been established unequivocally via application of X-ray crystallographic techniques.The results of alkali metal picrate extraction experiments suggest that neither 7 nor 9 is capable of functioning efficiently as an alkali metal cation extractant in solution.

Experimental Section
General Procedures.Melting points are uncorrected.Elemental microanalytical data were obtained by personnel at M-H-W Laboratories, Phoenix, AZ. High-resolution mass spectral data reported herein were obtained at the Mass Spectrometry Facility at the Department of Chemistry and Biochemistry, University of Texas at Austin by using a ZAB-E double sector high-resolution mass spectrometer (Micromass, Manchester, England) that was operated in the chemical ionization mode.Tetramethylsilane was used as internal standard for 1 H and 13 C NMR and CFCl 3 for 19 F NMR.

Preparation of 9.
A suspension of NaH (180 mg of a 60% suspension of NaH in mineral oil, 4.49 mmol) in dry THF (25 mL) under argon was cooled to 0 °C via application of an external ice-water bath.To this cooled solution was added dropwise with stirring a solution of 5 (826 mg, 1.50 mmol) in dry THF (25 mL) under argon during 1 h.After the addition of 5 had been completed, the external ice-water bath was removed, and the reaction mixture was allowed to warm gradually to ambient temperature while stirring during 1 h.The reaction mixture then was heated to reflux temperature, and a solution of 2,6-bis(bromomethyl)-1-fluorobenzene (8, 15 422 mg, 1.50 mmol) in dry THF (125 mL) was added dropwise with stirring during 12 h.The resulting mixture was refluxed during 4 days, at which time the reaction mixture was cooled to 0 °C via application of an external ice-water bath, and the reaction was quenched via careful, dropwise addition of cold water (1 mL) with stirring.The resulting mixture was concentrated in vacuo, and the residue was extracted into EtOAc (150 mL).The organic phase was washed sequentially with water (70 mL) and brine (80 mL), dried (MgSO 4 ), and filtered, and the filtrate was concentrated in vacuo.The residue was purified via column chromatography on silica gel by eluting with 25% EtOAc-hexane.Pure 9 (609 mg, 62%) was thereby obtained as a viscous oil; IR (film): 2930 (s), 2845 (s), 1605 (w), 1572 (w), 1445 (s), 1105 (vs), 742 (s), 655 cm -1 (m); 1   X-Ray structure of 7. All data were collected at 293(2) K on a Brucker SMART TM 1000 CCD diffractometer.The frames were integrated with the SAINT program package 18 by using a narrow frame algorithm.The structure was solved and refined by using SHELXTL. 19There is some disorder associated with the orientation of the methylene group on the cage moiety and with the side-chain, particularly in the vicinity of the CF 2 groups.This disorder was not pursued further, since the primary intent of this analysis was structural confirmation.The structure was verified by using PLATON. 20Crystal and refinement data are given in Table 2.

Table 2 .
X-ray data crystal and structure refinement data for 7