A fluorescent sensor for magnesium ions

A fluorescent sensor for magnesium ions
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  Pergamon Tetrahedron Letters 39 (1998) 5451-5454 TETRAHEDRON LETTERS A FLUORESCENT SENSOR FOR MAGNESIUM IONS Luca Prodi,* Fabrizio Bolletta, Marco Montalti, Nelsi Zaccheroni Dipartimento di Chimica G. Ciamician , Universitfi di Bologna, Italia Paul B. Savage,* Jerald S. Bradshaw, Reed M. Izatt Department of Chemistry and Biochemistry, Brigham Young University. Provo, UT 84602 Received 3 April 1998; revised 8 May 1998; accepted 12 May 1998 Abstract: Diaza-18-crown-6 ppended with two 5-chloro-8-hydroxyquinoline roups can serve as an effective chemosensor for Mg 2+. The modified macrocycle will fluoresce in the presence of Mg 2÷ but not with other alkaline earth ions at pH 7.2. Mg 2+ concentrations can be measured n the presence of Na 2+, K +, Ca 2+, Sr 2+ and Ba 2+. © 1998 Elsevier Science Ltd. All rights reserved. The ability to monitor analyte concentrations in real-time and real-space using chemosensors finds application in many fields including medical diagnostics, environmental control, cell biology, and electronics. 1 Typically, chemosensors are small molecules that are able to bind selectively and reversibly the analyte of interest with a concomitant change in a property of the system, such as redox potentials or absorption or fluorescence spectra. Of the various kinds of chemosensors, the fluorescent types present many advantages since luminescence measurements are usually very sensitive, low cost, easily performed, and versatile, l Of particular interest has been the measurement of the concentrations of alkaline earth cations in biological samples. Ca 2÷ and Mg 2+ can play important roles as intracellular messengers in the regulation of cell function. 2 Multiple fluorescent indicators have been developed for use in measuring Ca 2+ concentrations. 1,3 Fewer have been developed for measuring Mg 2÷ concentrations. 4 The fluorescent Mg 2÷ indicators that have been reported demonstrate poor selectivity for Mg 2+ over Ca 2+ and are useful only where the concentrations of Mg 2+ are much higher than those of Ca 2÷. We now report the ability of diaza-18-crown-6 appended with two 5-chloro-8-hydroxyquinoline-7-yl CHQ) groups (1) to serve as an effective chemosensor for Mg 2÷ in the presence of other alkali and alkaline earth cations. Compound 1 was prepared in a series of related macrocycles 5 and was found to have unique abilities to detect the presence of Mg 2÷, The series of compounds we are preparing are comprised of macrocycles covaiently linked to known l / x 9J ok___ o__ oH 1 chelating fluorophores and chomophores. The synthesis of macrocylic ligands appended with fluorescent or chromogenic chelators is a promising approach for developing metal-ion chemosensors because of the ion selectivity of macrocyclic ligands and the fluorescence and/or chromogenic response of the appended chelating groups. We have used 8-hydroxyquinoline groups as the chelating fluorophores in a number of new compounds due to their fluorescence modulation when complexed to certain metal ions. 6 The absorption characteristics of 8-hydroxyquinoline are infuenced by protonation of the nitrogen atom and deprotonation of the hydroxyl group. 7 Acid-base titration experiments with 1, followed spectrophotometrically, 8 showed that the pK a values for the deprotonation of the nitrogen atom and of the hydroxy groups in methanol-water (1:1 vol:vol) 9 solution were 2.8 and 10.2, respectively (Figure 1). We also observed that the presence of certain meud cations 0040-4039/98/ 19.00 © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(98)01070-3  5452 modified the apparent pK a values of the hydroxy groups in the CHQ ligands. Figure 1 shows the pH dependence of a methanol-water (h 1 vol:vol) solution containing 1 (5 x 10 -5 M) and Mg 2+ (2.7x10 -4 M). In the 1-Mg 2+ complex the second deprotonation process is shifted to much lower pH values. This change in pK a is presumably caused by chelation of Mg 2+ with the phenolic oxygen which increases the acidity of the phenolic proton. Deprotonation of both phenol groups on 1 concomitant with association with a divalent cation yields a neutral complex. This neutral complex with Mg 2+ was formed at pH values higher than 6. At pH 7.2, addition of equimolar amounts of Ni 2+, Cu 2+ or Zn 2+ to 1 also 27, 2.55 -- - 2.15 i~r- -'~ I 4~ A ',, 1.95 i * 4-- i 1.75 155 : • 1.35 ' - - ~ 1.15 - ~ J "~0.951 ; --~- 0.75 ........ 2 3 4 5 6 7 8 9 10 11 12 pH Figure 1. Absorbance of 1 (1 x 10 -5 M in methanol-water 1:1 vol:vol)) at various pH values: • - 1 alone, • - 1 with iMg2+(2.7 x 10-3 M). resulted in changes in the absorption spectrum of 1. These changes are consistent with deprotonation of the CHQ groups giving neutral complexes. In contrast, addition of equimolar amounts of K ÷, Na ÷, Ca 2÷, Sr 2÷, and Ba 2÷ did not cause changes in the absorption spectrum of 1. These results correlate well with the reported 5 ion selectivity demonstrated by 1, i.e., 1 selectively binds Mg 2÷ over other alkaline earth metals (log K a values (determined in methanol)in parentheses: Mg 2÷ (6.82), Ca 2÷ (5.31), Sr 2÷ (4.43) and Ba 2÷ (3.60)). The ligand also forms very stable complexes with Ni 2÷, Cu 2÷ and Zn 2÷ (log K a values (determined in methanol) of 11.4, 10.I and 5.2, respectively). Notably, calorimetric titration of CHQ with Mg 2÷ in methanol provided no measurable heat other than heat of dilution indicating that zSJ-/and or log K a is small. 5 Uncomplexed 1 gives a very weak luminescence band (~< 5 x 10 -5, t < 0.5 ns) centered at 540 nm in methanol/water (1:1 vol:vol) (Figure 2). This behavior is consistent with the luminescence properties of the parent neutral 8-hydroxyquinoline in protic solvents, where intra- and inter-molecular excited state proton transfer has been invoked to explain the high efficiency of the radiationless deactivation to the ground state. 7 Also, as is the case with the parent 8-hydroxyquinoline, no appreciable luminescence intensity increase was observed from pH 2 to 13 with uncomplexed 1. However, addition of Mg 2÷ to 1 (5 x 10 5 M) in a neutral (pH = 7.2) methanol/water (1:1 vol:vol) solution led to a strong enhancement of the luminescence band (O = 0.042, t = 7.4 ns) as shown in Figure 2. Upon association with Mg 2÷ and excitation at 395 rim, the fluorescence intensity of 1 increases by factor of a thousand. 8 The excitation spectrum of the complex strictly matches the absorption spectrum of l'Mg 2÷, suggesting that the observed fluorescence is due to neutral complex formation. In this case, an excited state proton transfer is precluded by the presence of the metal ion. The luminescence intensity v pH curve of 1-Mg 2÷ has the same profile observed with the absorption spectra, indicating that the apparent association constant for the Mg 2÷ ion of the excited state is similar to that of the ground state. We believe that this is due to kinetic features, since the complexation-decomplexation process should be slower than the decay to the ground state. Contrary to what was observed with Mg 2÷, no luminescence increase was detected upon adding K ÷, Na ÷, Ca 2÷, Sr 2÷ or Ba 2÷ to 1 (5 x 10 -5 M) at pH 7.2 in methanol-water (1:1 vol:vol). For these cations, the lack of luminescence increase can be attributed to the absence at this pH of formation of neutral complexes (i.e., complexes in which deprotonation of the hydroxy group has occurred). Also, addition of Cu2+and Ni 2÷ to a solution of 1 provided no increase in luminescence. Complexation of 1 with Cu 2÷ or Ni 2÷ yields a neutral complex; however, in these complexes, energy and electron transfer processes are accessible and provide a fast deactivation route to the ground state. This behavior of 1 with Cu 2÷ and Ni 2÷ was not unexpected since  5453 complexes of Cu 2÷ and Ni 2+ with r other 8-hydroxyquinoline 250 - derivatives have also demonstrated a q" Mg2 lack of fluorescence. 6 In contrast, -'. additi°n°fZn2+t°l resulted in a /~2°0- /~ luminescent complex, but with a fluorescence quantum yield eight [ 150_ f~f/// .,~Nkk~k times lower than that of the 1-Mg 2÷ complex. Additionally, the K a of 1 with Mg 2+ is much larger than with / ~ 10o - /tiff/ "~. ~\~ Zn 2+ (nearly two orders of ]i magnitude). 5 Consequently, Zn ~÷ did not interfere with observation of 50 1-Mg 2+ complex formation via fluorescence unless the Zn2+ [ o concentration far exceeded that of [ 400 450 500 550 600 650 Mg2+" [ ~. (nm) To further explore the utility I Figure 2. Fluorescence spectra of 1 (1 x 10 5 M) in methanol-water of 1 as an ion-selective fluorescent I (1:1 vol:vol) with increasing amounts of Mg 2+. k~x= 393 rim. chemosensor for Mg 2+, we performed titration experiments with 1 and Mg 2+ in the presence of other metal ions. Our intent was to demonstrate that measurement of Mg 2+ concentrations was possible in a matrix complicated by alkali and alkaline earth cations. A solution of 1 (5 x 10 5 M) in methanol/water (l:l vol:vol) at pH 7.2 was prepared containing Na + (5 x 10-3 M), K + (1 x 10- 3 Air), Ba 2+ (I x 10- 3 M), Sr 2+ (1 x 10 3 M), and Ca 2+ (1 x 10 4 M). Into this solution was titrated Mg 2+ and the titration was monitored via fluorescence. The tritration curve shown in Figure 3 was obtained. Notably, the fluorescence intensity reached a maximum when one equivalent of Mg 2. was added, suggesting that fluorescent intensities could be directly correlated to Mg 2+ "~ 100 '- 80 80-- t_ I 40 r~ ~. 20 ,~ 0t • 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Equivalents of Mg 2÷ Figure 3. Titration of 1 and Na + (5 x 10- 3 M), K + (1 x 10 3 M), Ba 2+ (l X 10- 3 M), Sr 2+ (l x 10 3 M), and Ca 2+ (1 x 10 -4 M3 in methanol- water (I:1 vol:vol) with Mg 2+. kex= 393 nm, ~.em 530 nm. concentrations. The lack of interference from the other metal ions present can be ascribed to their lower association constants with 15 and low quantum yields for the charged complexes that form from Na +, K ÷, Ba 2+, Sr 2+, and Ca 2+ with 1 at this pH. We have demonstrated that 1 possesses characteristics for being considered an efficient fluorescent chemosensor for Mg 2+ ions, i.e., good selectivity and high affinity towards Mg 2+ at a range of pH values (>6), and a very large enhancement in fluorescence upon chelation. The increased fluorescence appears to require  5454 formation of a neutrai complex of 1 with Mg 2+, and formation of this neutral complex is unique to Mg 2+ among the alkaline earth cations. Compound 1, acting as an ion-selective chemosensor for Mg 2+, may find use in determining Mg 2+ concentrations in biological samples and, if immobilized in a solid support, may be incorporated into sensory devices for measurement of Mg 2+ concentrations in aqueous solutions. Acknowledgement We thank the Italian Minister for Research (MURST) and the Universita' di Bolonga (Funds for Selected Topics) for financial support (LP, FB, MM, NZ) and also the Office of Naval Research for funding (PBS, JSB, RMI). In addition, we thank Silvia Pivari for performing several experimental measurements. REFERENCES 1. (a) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A. J. M.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997, 97, 1515. (b) Fluorescent Chemosensorsfor Ion and Molecule Recognition, Czarnik, A.W., ed., A.C.S.: Washington, D. C., 1992. 2. For examples see: (a) Tsien, R. Y. Annu. Rev. Biophys. Bioeng. 1983, 12, 91. and refs cited therein. (b) Grubbs, R. D.; Maguire, M. E. Magnesium 1987, 6, 113. (c) Henquin, C.; Tamagawa, T.; Nenquin, M.; Cogneau, M. Nature 1983, 301, 73. 3. Grynkiewicz, G.; Poenie, M.; Tsien, R. Y. J. Biol. Chem. 1985, 260, 3440. 4. For examples see: (a) Raju, B.; Murphy, E.; Levy, L. A.; Hail, R. D.; London, R. E. Am. J. Physiol. 1989, 256, C540. (b) Morelle, B.; Salmon, J.-M.; Vigo, J.; Viallet, P. Photochem. PhotobioL 1993, 58, 795. 5. Bordunov; A. V.; Bradshaw, J.S.; Zhang, X.X.; Dalley, N.K.; Kou, X.; Izatt, R.M. Inorg. Chem. 1996, 35, 7229. 6. For example see: (a) Sandell, E. B.; Onishi, H. in Photometric Determination of Trace Metals, Elving, P. J.; Winefordner, J. D., eds., John Wiley & Sons: New York, 1978, vol. 3, pp. 415-447. (b) Soroka, K.; Vithanage, R. S.; Phillips, D. A.; Walker, B.; Dasgupta, P. K. Anal Chem. 1997, 59, 629. 7. (a) Bardez, E.; Devol, I.; Larrey, B.; Vaieur, B. J. Phys. Chem. 1997, 101, 7786. (b) Goodman, M.; Wehry, E.L. Anal. Chem. 1970, 11, 1178. 8. The solvents, methanol and ethanol (UVASOL) from Merck Co. were used as received. Water was Millipore grade. Absorption spectra were recorded with a Perkin Elmer 2~ 16 spectrophotometer. Uncorrected emission and corrected excitation spectra were obtained with a Perkin Elmer LS 50 spectrofluorometer. The fluorescence lifetimes (uncertainty _+ 5%) were obtained with an Edinburgh single-photon counting apparatus, in which the flash lamp was f'flled with D2. Luminescence quantum yields (uncertainty + 15%) were determined using quinine sulphate in 1 M aqueous H2SO4 (O = 0.546) 10 as a reference. In order to allow comparison of emission intensities, corrections for instrumental response, inner filter effects, and phototube sensitivity were performed) 1 A correction for differences in the refraction index was introduced when necessary. UV and emission spectra were run on 3 ml of a 5 x 10 5 M methanol/water (1:1 vol:vol) solution of the crown ether. Aliquots (10 ml) of 2.5 x 10 3 M salt solution were then added with a micro syringe and spectra recorded. The intensity was read at the maximum of the luminescence band. 9. The behavior of 1 in the presence of metal cations was measured in methanol-water (1:1 vol:vol) due to the low solubility of 1 in water. Nevertheless, the ion selectivities of 1 are expected to be the same in water as they are in the mixed aqueous solvent system (for an example of ion selectivities of macrocycles in methanol-water mixtures compared to selectivities in water see: Zhang, X. X.; Izatt, R. M.; Krakowiak, K. E.; Bradshaw, J. S. Inorg. Chim. Acta 1997, 254, 43). Metal complexes of 1 with Mg 2÷ are expected to fluoresce in water (see ref. 6b). 10. Meech, S.R.; Phillips, D. J. Photochem. 1983, 23, 193. 11. Credi, A.; Prodi, L. Spectrochimica Acta, PartA 1998, 54, 159.
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