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Selectivity of Lariat Ethers with Tunable Proton Ionizable Pendant Amide Groups by ESI-MS

Selectivity of Lariat Ethers with Tunable Proton Ionizable Pendant Amide Groups by ESI-MS Sheldon M. Williams and Jennifer S. Brodbelt Department of Chemistry and Biochemistry University of Texas at Austin, Austin, TX 78712. Overview

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Selectivity of Lariat Ethers with Tunable Proton Ionizable Pendant Amide Groups by ESI-MS

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  1. Selectivity of Lariat Ethers with Tunable Proton Ionizable Pendant Amide Groups by ESI-MS Sheldon M. Williams and Jennifer S. Brodbelt Department of Chemistry and Biochemistry University of Texas at Austin, Austin, TX 78712

  2. Overview • Purpose: Determine alkali metal cation selectivities of ten lariat ethers with amide pendant groups by ESI-MS. Study effects of methanol/water solvent ratio and acidity/basicity on selectivity. • Methods: • Novel lariat ethers synthesized by Prof. Richard Bartsch of Texas Tech University, Lubbock, Texas • Single host with two-fold excesses of multiple metals analyzed for each lariat ether • 5 x 10-5 M lariat ether and 1 x 10-4 M metal salts • Solvent composition ratios of 100/0, 90/10, 75/25/ and 50/50 methanol/water (v/v) • Acidic versus basic conditions set using HCl and hydroxides of the alkali metals • Finnigan ion trap with SWIFT axial modulation and an electrospray source • Results: • Na+ selectivity greatest with geminal N,N-dipentyl oxyacetamide and propyl pendant arms • K+ selectivity greatest with primary amine pendant arm • Propyl group increases Na+ selectivity • Greater solution acidity increases Na+ selectivity Introduction Lariat ethers with pendant amide groups (LEAs) have shown promise of being highly selective for particular metal ions [1-4]. This makes them good candidates for study in the development of new ion sensors with improved selectivity. In this study we report alkali and alkaline earth metal binding selectivities of ten of these lariat ethers and dibenzo-16-crown-5 (Figure 1) by use of electrospray ionization mass spectrometry. Solvent effects on metal selectivity are examined for several methanol/water solutions, as well as the influence of the acid/base nature of the solution. The validity of determination of selectivities in this study by electrospray ionization mass spectrometry is established by analogous experiments with hosts with known binding constants for the metals and solutions used.

  3. O O O O O O O H H H O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O Figure 1. Lariat Ether with Amide Pendant Groups (LEAs) and Reference Compounds O H OCH2CNHC3H7 OCH2CNH2 18-Crown-6 Dibenzo-16-Crown-5 LEA403 LEA445 O O O O C3H7 OCH2CN(C2H5)2 H H OCH2CNHC5H11 H OCH2CN OCH2CN(C2H5)2 O O O O O LEA501 LEA471 LEA473 LEA459 O O O O H H OCH2CN(C2H4OCH3)2 C3H7 OCH2CN O H OCH2CN(C5H11)2 OCH2CN(C5H11)2 O O O O O LEA607 LEA585 LEA543 LEA473cyc

  4. Methods Solutions containing a single host with two-fold excesses of multiple metals were analyzed for each lariat ether. The concentration of host and each metal were 5 x 10-5 M and 1 x 10-4 M, respectively. Solvent composition ratios of 100/0, 90/10, 75/25, and 50/50 methanol/water (v/v) were analyzed for two of the lariat ethers. Various –log[H+] and –log[OH-] values were set by the addition of HCl or hydroxides of the alkali metals. Solutions are neutral unless otherwise indicated. All mass spectrometry experiments were performed on a Finnigan ion trap with SWIFT axial modulation and an electrospray source. Water was high purity 18 M, purified on site. Methanol was spectral grade from Fisher, and all lariat ethers were synthesized in the lab of Prof. Richard Bartsch. Other chemicals were 99%+ pure from Sigma-Aldrich and used as received. Results Validation of Selectivity Determination Method Though the validity of determining host-guest selectivities by mass spectrometry has been confirmed in numerous past studies by this group for macrocycles with alkali and various transition metals [5-10], new experiments were performed to validate this method for the inclusion of the alkaline earth metal cations, Mg and Ca, and the variety of methanol/ water solvent systems used in this study. As 18-crown-6 is a host for which extensive host-guest binding constant data is available in the literature [11], this macrocycle was used as the model host molecule. For example, the intensities of (18-crown-6 + Na)+ and (18-crown-6 + K)+ complexes were examined individually to estimate ESI spray efficiencies, and then mixtures containing 18-crown-6 with both metals were analyzed and corrected to reflect solution equilibria. Figure 2 shows ESI-mass spectra obtained for 18-crown-6 with sodium and potassium chloride in pure methanol. Table 1 compares the relative intensities of the signals for the different complexes to the calculated solution equilibrium distributions in solution complexes based on binding constants found in the literature for 18-crown-6 with either (i) sodium and potassium at a variety of methanol/water solvent systems or (ii) with magnesium and calcium in methanol. These results show that the relative signal intensities for complexes with these metals can be used to semi-quantitatively determine selectivities for solutions ranging from pure methanol to 75/25 methanol/water. Estimated error in both mass spectrometrically determined and theoretically calculated distributions in Table 1 are similar, with the errors in peak height uncertainty and in literature binding constant determinations of about +10% relative error.

  5. Table 1. Results for Comparisons of Distribution of Metal Complexes from Mass Spectra Signal Intensities and Calculated log K values from Literature

  6. Figure 2. Determination of Selectivity by ESI-MS for 18-Crown-6 with NaCl and KCl in Pure Methanol Theoretical Ratio CNa/CK = 0.934 Experimental Ratio INa/IK = 1.09

  7. Corrected Experimental Distribution Na vs K 16% vs 84% Experimental Distribution Na vs K 19% vs 81% Theoretical Distribution Na vs K 14% vs 86%

  8. Observed Selectivities for Lariat Ethers with Amide Pendant Groups for Alkali and Alkaline Earth Metal Cations in Methanol The signal intensity distributions for dibenzo-16-crown-5 and the ten lariat ethers with two-fold excesses of LiCl, NaCl, KCl, RbCl, and CsCl in methanol is shown in Figure 3A. Dibenzo-16-crown-5 and all the lariat ethers with amide pendant arms showed a selectivity order for alkali metal ions of Na > K > Rb > Cs  Li. The percent of lariat ether bound to Li, Rb, or Cs showed little fluctuation throughout the series of macrocycles, with Rb, Cs, and Li making up about 15%, 10%, and 5% of total complex, respectively. Figure 3A. Trends for Selectivities of Lariat Ethers with Amide Pendant Groups towards Alkali Metal Cations

  9. 1.36 1.36 1.96 1.96 2.66 2.66 3.30 3.30 A A A A 2.98 2.98 A A A A A A A A A A A A A A A A Na Na + + Li Li + + K K + + Cs Cs + + Rb Rb + + Dibenzo Dibenzo - - 16 16 - - Crown Crown - - 5 5 Dibenzo Dibenzo - - 16 16 - - Crown Crown - - 5 5 H H H H H H H H O O O O O O O O O O O O O O O O O O O O 2.0 2.0 - - 2.4 2.4 A A A A This selectivity order follows the trend expected from the ionic diameter of the metal cations versus the inner diameter of the dibenzo-16-crown-5 ring (Figure 3B). However, a large degree of variation was seen in the Na/K selectivity of the lariat ethers (see Figure 4), with Na/K selectivity ranging from 1.2 to 2.8. These variations in Na/K selectivity are primarily due to the interaction of the pendant arm or arms with the sodium and potassium ions.[5] Figure 3B. Diameters of Alkali Metal Ions and Dibenzo-16-Crown-5 Cavity

  10. In pure neutral methanol, the addition of amide pendant arms with one alkyl group does not enhances the Na/K selectivity versus that of dibenzo-16-crown-5 with no pendant arms. However, “N, N-” substituted amide pendant arms show enhanced Na/K selectivity relative to that of dibenzo-16-crown-5. LEA585, with two propyl groups attached to the amide and a propyl group geminal to the oxyacetamide pendant arm shows the greatest Na/K selectivity. Enhancement in Na/K selectivity due to the presence of the geminal propyl arm is observed for the higher Na/K selectivity value for LEA501 versus LEA459 and LEA585 versus LEA543. The enhanced Na/K selectivities of LEA585 and LEA607 compared to the other lariat ethers appears to be due to the larger aliphatic or ether groups on the amide group. The sodium ion, which nests within the crown ether cavity of the lariat ethers Figure 4. Trends for Na/K Selectivities of Lariat Ethers with Amide Pendant Groups

  11. Figure 4B. Recent Data: Trends for Mg/Ca Selectivities of Lariat Ethers with Amide Pendant Groups is not as adversely affected by interactions with the aliphatic R groups as the potassium ion perched above the cavity, thus, the relative difference in binding affinity for sodium versus potassium ion is increased. The poorest Na/K selectivity involves the lariat ethers with one or two N-H bonds at the neutral amide group (LEA403, LEA445, and LEA473). This suggests the repulsion of K versus Na in the lariat ethers with 3 N-R bonds (R = hydrocarbon group) and no N-H bonds at the amide group is due more to steric factors than charge repulsion, as the hydrogens of the N-H would carry a larger positive charge density than the R groups. These results agree with relative selectivities previously observed for LEA459 and LEA501 by the Bartsch research group in acidic aqueous solution by ion selective electrode. [4]

  12. Effect of Solution Acidity/Basicity on Metal Selectivites of Lariat Ethers with Amide Pendant Groups in Methanol Because some of the macrocycles are ionizable, the acid/base nature of the solution can play a major role on binding properties. Thus, ESI-MS was used to analyze solutions in which the hydronium and hydroxide content varied. Figure 5A shows ESI-mass spectra for LEA459 (N,N-diethyldibenzo-16-crown-5-oxyacetamide; pKa about 8-9), at a variety of acidic/basic conditions. An alkali selectivity order of Na > K > Rb > Li with a Na/K selectivity of approximately 1.7 persists in basic or neutral solutions. However, going from –log[H+]T values of 5 to 3, the Na/K selectivity increases to greater than 10. It is hypothesized that in basic and mildly acidic solutions, the alkali metals are able to effectively compete with protonation of the amide nitrogen due to the pre-organization occurring because of the close proximity of the amide pendant arm to the metal ion binding macrocyclic cavity of the lariat ether. Furthermore, as the –log[H+]T value progresses from 5 to 3, only the sodium ion, with a size most suited to both the ring cavity diameter and coordination with the amide nitrogen over the ring, is able to compete successfully with protonation. Very similar results were obtained for LEA543. Consequently, these lariat ethers with amide pendant groups become highly sodium selective under moderately acidic solution conditions (-log[H+]T 3). In order to confirm that this large increase in Na/K selectivity at –log[H+]T = 3 was indeed due to a selectivity change rather than the effect of the acidic conditions on the electrospray process, 12-crown-4 was analyzed at neutral and acidic conditions (Figure 5B). The degree of change in Na/K selectivity for 12-crown-4 from neutral to –log[H+]T = 3 is very small, though it appears must of the 12-crown-4 becomes protonated. This is supporting evidence that the observed change in signal ratios for sodium versus potassium complex of LEA459 and LEA543 is due to a dramatic change in selectivity rather than an artifact of the electrospray process.

  13. Figure 5A. 2:2:2:2:1 LiCl:NaCl:KCl:RbCl:LEA459 in Methanol at Different Acid/Base Conditions (L = LEA459)

  14. Figure 5B. 2:2:2:2:1 LiCl:NaCl:KCl:RbCl:12-Crown-4 (12C4) in Methanol at Different Acid/Base Conditions m/z 12-crown-4 m/z

  15. Solvent Effects on Metal Selectivities of Lariat Ethers with Amide Pendant Groups ESI-mass spectra of LEA459 with alkali metal chlorides in 100% methanol, 75/25 methanol/water, and 50/50 methanol water (v/v) are shown in Figure 6. The general selectivity order of Na > K > Rb > Li is maintained as the solvent system becomes increasingly aqueous in nature. The variations in selectivity appear to be minor, with the apparent Na/K selectivity and Na/Rb selectivity increasing slightly. This small increase in Na/K selectivity may be due to the greater availability of protons that can be acquired by the amide arm of the lariat ethers in near-neutral pH solutions with high percentages of water compared to the solutions made with only high purity methanol as a solvent, enhancing the protonation related increase in Na/K selectivity which was observed in acidic, pure methanol solvent solutions.

  16. Figure 6. 2:2:2:2:1 LiCl:NaCl:KCl:RbCl:LEA459 at Different Methanol/ Water Ratios (L = LEA459)

  17. Conclusions The lariat ethers with amide pendant arms show a selectivity order towards alkali metal ions of Na > K > Rb > Cs > Li, with poor relative selectivity for Rb, Cs, and Li. The addition of an N,N-dipentyl oxyacetamide group and a propyl group as geminal side arms on a dibenzo-16-crown-5 lariat ether appears to enhance the Na/K selectivity. These results suggest areas for further study. Greater sodium selectivity might be achieved by adding tert-alkyl groups to similar pendant arms to greater enhance sodium selectivity. Alternatively, adding unsubstituted primary amine or amide groups as pendant arms may further enhance potassium binding. Protonation of the amide nitrogen also appears to enhance sodium selectivity of the lariat ethers, probably by creating charge repulsion towards metal ions which nest more poorly than Na+ in the dibenzo-16-crown-5 cavity of the lariat ethers. Further study of solvent and acidity effects on alkali metal ions as well as alkaline earth and transition metals will be undertaken. Acknowledgements Funding for this work was provided by the Welch Foundation, the National Science Foundation, and the Texas Advanced Technology Program.

  18. References 1. Kempen, E.C., Brodbelt, J.S., Bartsch, R.A., Jang, Y., and Kim, J.S., Anal. Chem. 71, (1999), 5493-5500. 2. Bartsch, R.A., Lu, J., Ohki, A., J. Incusion Phenom. Mol. Recognit. Chem., 32 (1998),133–150. 3 Ohki, A., Iwaki, K., Naka, K., Maeda, S., Collier, J., Jang, Y., Hwang, H-S., Bartsch, R.A., Electroanalysis, 8 (1996), 615-618. 4. Ohki, A., Maeda, S., Lu, J.P., Bartsch, R.A., Anal. Chem. 66 (1994), 1743-1746. 5. Williams, S., Blair, S.M., Brodbelt, J.S., Huang, X., Bartsch, R.A., Int. J. Mass Spectrom., 212 (2001), 389-401. 6. Marchand, A. P., Huang, Z., Chen, Z., Hariprkasha, H., Namboothiri, I.N.N., Brodbelt, J.S., and Reyzer, M.L., J. Heterocyclic Chem., 38 (2001), 1361-1368. 7. Kempen, E. C., Brodbelt, J.S., Bartsch, R., Blanda, M.T., Farmer, D.B., Anal. Chem., 73 (2001), 384-390. 8. Reyzer, M.L., Brodbelt, J.S., Marchand, A.P., Chen, Z., Huang, Z., Namboothiri, I.N.N., Int. J. Mass Spectrom., 204 (2001), 133-142. 9. Blair, S., Brodbelt, J., Marchand, A.P., Chong, H-S., Alidhodzic, S., J. Am. Soc. Mass Spectrom., 11 (2000), 391-394. 10. Kempen, E., Brodbelt, J., Anal. Chem., 72 (2000), 5411-5416. 11. Izatt, R.M., Pawlak, K., Bradshaw, J.S., Chem. Rev., 91 (1991), 1721-2085.

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