OCH 2 CH 2 OCH 2 CH 2 OCH 3

1. O C H O C H C H 3 3 3 7 O O O O O O O O O O Na+ 1 Na+ Na+ 2 d1 O C H C H O C H O C H C H O C H C H 2 2 3 H 2 2 3 3 7 1 3 5 d2 A) 99% Methanol / 1% Chloroform (LE1 + Na)+ (LE1 + K)+ 100 (LE1 + Rb)+ (LE1 + Li)+ H 0 100 200 300 400 500 600 O O O O B) 75% Methanol / 25% Chloroform (LE1 + Na)+ (LE1 + K)+ 100 K+ K+ K+ (LE1 + Rb)+ (LE1 + Li)+ 0 100 200 300 400 500 600 C) 50% Methanol / 50% Chloroform O O O O 100 (LE1 + Na)+ (LE1 + K)+ (LE1 + Rb)+ (LE1 + Li)+ O O 0 100 200 300 400 500 600 D) 5% Methanol / 95% Acetonitrile (LE1 + Na)+ (LE1 + K)+ 100 (LE1 + Rb)+ (LE1 + Li)+ 3 4 0 100 200 300 400 500 600 Na+ K+ O C H C H O C H C H O C H C H 2 2 2 2 3 3 7 O O O O O H OCH2CH2OCH2CH2OCH3 5 6 O O R1 R2 O O O d2 d1 Determination of Alkali Metal Selectivities of Dibenzo-16-Crown-5 Lariat Ethers with Ether Pendant Groups Using ESI-MS Sheldon M. Williams*, Sheryl M. Blair and Jennifer S. Brodbelt Department of Chemistry and Biochemistry The University of Texas at Austin, Austin, TX 78712 • Overview • Purpose: Determine alkali metal cation selectivities of six lariat ethers with ether pendant groups by ESI-MS in four methanolic solvent systems. • Methods: • ESI-MS of methanolic solutions • Customized Finnigan ion trap mass spectrometer • Ab initio molecular modeling with RHF 3/21G* method • Results: • Na+ selectivity greatest with the dioxapentyl substituent • K+ selectivity greatest with dioxaoctyl substituent • Propyl group increases Na+ selectivity • Less polar solvents reduce Na+/K+ selectivity Methods Solutions containing a single host with multiple metals were analyzed for each lariat ether in solvent composition ratios of 99/1, 75/25, 50/50, and 25/75 methanol/ chloroform and 5/95 methanol/ acetonitrile. The concentration of host and each metal were 5 x 10-5M and 1 x 10-4M, respectively. All mass spectrometry experiments were performed on a Finnigan ion trap with SWIFT axial modulation and an electrospray source based on a design developed by Oak Ridge National Laboratories involving a differentially pumped region containing ion focusing lenses [6]. Neither a heated desolvation capillary nor a sheath flow gas was used. The Harvard syringe pump system operated at a flow rate of 3.0 l/min for all solutions. The ESI needle voltage was 3.0 kV. Molecular mechanics conformational searches were performed using MMFF (Merck) force fields followed by ab initio calculations using a Restricted Hartree-Fock model at the 3-21G* level of theory with Spartan 5.0 software operated on a Silicon Graphics O2 computer workstation with an IRIX 6.5 operating system and 300 MHz MIPS R5000 processor. Inter-atomic Distance Calculations The results of molecular modeling and ab initio calculations for lariat ethers 1, 3, 4,and 5 with Na+ and K+ are presented in Table 2 together with plots of their cross-ring distances in Figure 8. Simultaneously, the other cross-ring distance (d2) increases for the Na+ complexes from 1 to 4, as the Na+/K+ selectivity correspondingly increases from about 1.3 to 2.5, then decreases for (5 + Na)+ as the Na+/K+ selectivity drops. By comparison, there is comparatively little change in the ring sizes of the K+ complexes with variation in pendant groups. The compaction of the 16-crown–5 ring for the (5 + Na)+ complexes that mirrors the drop in selectivity may occur because the pendant arm retains the ion above the ring and the oxygens crowd beneath it, as shown in Figure 5, to maximize interactions. Models calculated by ab initio methods are shown for the complexes of Na+ with 1, 3, and 5 in Figure 5, K+ with 1, 3, and 5 in Figure 6, and Na+ and K+ with 4 in Figure 7 . Because the diameter of the cavity of the 16-crown-5 ring of the lariat ethers is slightly larger than Na+, but smaller than K+, it is generally observed that Na+ is nested within the crown ether ring while K+ perches above it. Table 2 RHF 3-21G* Ab initio Calculations for Lariat Ethers 1-6 with Na+ and K+ Figure 3 summarizes the complete set of ESI-MS results obtained for the distributions of alkali metal cation complexes of the six lariat ethers, as measured by mass spectral peak intensities. Since complexation of either Li+ or Rb+ is generally less favorable than complexation of Na+ or K+ for each of the lariat ethers, the Na+/ K+ selectivities provide the most relevant comparisons, as highlighted in Figure 4. generally observed for 1 and 2. Diminution of the Na+/K+ selectivity with reduced solvent polarity for 1 and 2 is due mainly to increases in complexation of both K+ and Li+ relative to Na+ complexation (see Figure 3). The size of Na+ is most similar to the cavity size of the 16-crown-5 ring, while the other ions have poorer fits which allow greater accessibility and potential for interaction with solvent molecules. Thus, there are greater enhancements in the interactions of the oxygen atoms of the 16-crown-5 cavity with Li+ and K+ in the less polar solvents, with the methoxy group having a minor influence on complexation. Conclusions For the six lariat ethers studied in the present report, the presence of a dioxapentyl group in conjunction with a propyl sidearm (i.e., in 4) creates the most Na+ selective lariat ether. Addition of a longer trioxaoctyl pendant group results in a preference for complexation of K+ over Na+ because of optimization of interactions between the metal ion and the oxygen atoms of the trioxaoctyl group. Addition of a second sidearm, a propyl group, regenerates Na+ selectivitybecause of a greater degree of pre-organization of the cavity in conjunction with optimization of the anchoring interaction with the metal ion provided by the ether pendant group. Decreases in polarity/dielectric constant of the solvent media generally lowers the Na+/K+ selectivity, possibly due to favorably increasing the electrostatic interaction between K+ and the 16-crown-5 ring while the Na+ interactions with the ring are comparatively little affected. Ab initio calculations show that the addition of the dioxapentyl or trioxaoctyl group pulls Na+ above the crown ether ring oxygens, increasing interaction with the former at the expense of interaction with the latter. Figure 3 Variations in Metal Ion Selectivity for Lariat Ethers in Various Solvent Systems Introduction The use of electrospray ionization – mass spectrometry (ESI-MS) [1-4] has proven to be successful for the analysis of a wide variety of non-covalently bound complexes. For determination of binding selectivities in host-guest chemistry, the intensities of complexes produced by ESI of solutions containing defined concentrations of one host and multiple guests are compared. ESI-MS analysis of binding selectivities has some advantages over the more conventional potentiometric, spectrophotometric and NMR titrimetric methods [5], such as reduced sample consumption, tolerance of a wide variety of solvent conditions and reduced analysis times. In this study, the alkali metal selectivities of six lariat ethers (Figure 1) were evaluated in different solvent systems by ESI-MS. All six of the lariat ethers have the same dibenzo-16-crown-5 skeleton, but with one or two substituents at the same bridging carbon position. The first subsituent consists of an ether of varied length (methoxy, 1,4-dioxapentyl, or 1,4,7-trioxapentyl), and the second consists of either a hydrogen or a propyl geminal group. The binding selectivity trends obtained are correlated with the number of oxygen atoms in the pendant ether group, the presence of a geminal propyl group, and the polarity of the solvent environment. Selectivities of Lariat Ethers In 99% methanol/1% chloroform solution, lariat ethers 1, 3, 4,and 6 show the same selectivity trend: Na+ > K+ > Rb+ > Li+, while for 2 and 5 the order of Na+ and K+ is reversed.Lariat ether 3 exhibits a modest increase in Na+/K+ selectivity compared to 1 and 2, presumably because the longer dioxapentyl ether pendant group can interact favorably to further stabilize the binding of Na+ as it nests within the dibenzo-16-crown-5 cavity, illustrated by the pendant arm of 3 hovering over the Na+ ion in Figure 5. Lariat ether 4 shows a further increase in Na+/ K+ selectivity and has the greatest Na+ selectivity of all of the six lariat ethers in this study. The Na+ selectivity is enhanced for 4 because the propyl group enforces the conformation of the dioxapentyl group relative to the cavity, thus enhancing the exclusion of K+, due to its larger size and perched position over the cavity, as illustrated in Figure 7. For 5 and 6, it was not intuitively obvious whether a longer ether pendant group (i.e. trioxaoctyl) would further anchor Na+ in the cavity or enhance the stabilization of K+. The ESI-mass spectrometric results confirm the latter for 5, with a preference for complexation of K+ over Na+. It is apparent from Figures 5 and 6 that the larger surface area of the K+ ion above the 16-crown-5 ring of 5 can accommodate all three oxygens of the trioxaoctyl group better than Na+. Addition of a geminal propyl group for 6 reverses the selectivity of 5. Apparently, the propyl group in 6 does not assist the trioxaoctyl group in stabilizing the larger K+ ion because pushing of the trioxaoctyl group further towards the 16-crown-5 cavity reduces the encapsulation volume to a size more amenable to Na+ complexation. Figure 5 Sodium Complexation of Lariat Ethers 1, 3, and 5 Results: Alkali Metal Cation Selectivities of Lariat Ethers Figure 2 illustrates an example of the mass spectra obtained in the four methanolic solvent systems for lariat ether 1. In this case, the selectivity varies in the different solvents, as rationalized later, but complexation with Na+ is always preferred. 1 3 5 Figure 8 Variations In Size of Lariat Ether’s 16-Crown-5 Ring Acknowledgements: The laboratory of Dr. Richard A. Bartsch, Department of Chemistry and Biochemistry, Texas Tech University, is gratefully acknowledged for synthesizing the lariat ethers used in this study. The National Science Foundation (CHE-9820755), the Welch Foundation (grants D-775 and F-1155) and the Texas Advanced Technology Program (003658-0206) are gratefully acknowledged. Figure 2 ESI Mass Spectra of Lariat Ether 1 with LiCl, NaCl, KCl and RbCl (1:2:2:2:2) Figure 6 Potassium Complexation of Lariat Ethers 1, 3, and 5 Figure 1 Lariat Ether Structures Figure 4 Variations in Na+ versus K+ Selectivity in Various Solvent Systems References 1)Yamashita, M.; Fenn, J.B.; J. Phys. Chem,1984, 88, 4451. 2)Fenn, J.B.; Mann, M.; Meng, C.K.; Wong, S.F.; Whitehouse, C.M.; Mass Spectrom. Rev.,1990, 9, 37. 3)Smith, R.D.; Loo, J.A.; Edmonds, C.G., Barinaga, C.J.; Udseth, H.R.; Anal. Chem.,1990, 62, 882. 4)Cole, R.B., Ed., Electrospray Ionization Mass Spectrometry, Wiley- Interscience, New York, 1997. 5)Martell, A.E., Hancock, R.D., Chapter 7: "Stability Constants and Their Measurement", Metal Complexes in Aqueous Solutions, Plenum Press: New York, 1996. 6)Van Berkel, G.J.; Glish, G.L.; McLuckey, S.A.; Anal. Chem. 1991, 62,1281. 7)Abraham, M.H., Liszi, J., J. Chem. Soc., Faraday Trans. 1, 1978, 74, 1604. Solvent Effects As shown in Figure 4, solvent composition has a much greater effect on Na+/K+ selectivity for 1 and 2 than for 3-6, confirming that the ether pendant group plays an important role in shielding the bound metal ion from external solvent changes. A large shift towards higher Na+ selectivity is seen for 1 and 2 in the 5% methanol/ 95% acetonitrile solution, compared to the 99% methanol/1% chloroform solutions, primarily because Na+ has a larger decrease in solvation energy in acetonitrile vs. methanol compared to the change in solvation energy for K+ [7]. Figure 4 also shows that in the less polar 75% methanol/25% chloroform, 50% methanol/50% chloroform, a recurring loss in the Na+/K+ selectivity with decreasing solvent polarity is Figure 7 Complexation of Na+ and K+ by Lariat Ether 4 As shown in Figure 8, the distance between the inner carbons of the two opposing aryl rings (d1) as well as the cross-ring distance between the carbon to which the pendant groups are attached and the crown ether ring oxygen opposite it (d2) give an indication of the cavity sizes of the lariat ethers, as influenced by the associated pendant group(s). For instance, the distance between the aromatic rings (d1) decreases slightly from (1 + Na)+ to (4 + Na)+, then drops dramatically from (4 + Na)+ to (5 + Na)+, indicating a compaction of the 16-crown-5 ring. For 4 and 5 in 99% methanol, the corresponding Na+/K+ selectivity likewise drops significantly from about 2.5 to about 0.8. (6) (7) (8) (1) (2) (3) (5) (4)