Norfloxacin-derivative functionalized octamolybdate: unusual carbonyl coordination and acidity sensitive luminescence

Abstract

A novel γ-type octamolybdate functionalized by decarboxylated norfloxacin (dNF), (dNF)₂[γ-Mo₈O₂₆(dNF)₂]·10H₂O (1), has been synthesized. In the broad range of acidic solutions, even in the pH < 0 range, the fluorescent intensities of 1 almost linearly changed with acidity, indicating that a solution of 1 could be used as an acidity fluorescent sensor. The enhancing and quenching behavior also makes complex 1 a potential acid–base switch system. The successful synthesis of 1 demonstrates a new acidity sensor based on a fluorescent medicine and polyoxometalate anions.

---

Polyoxometalates (POMs), a unique class of fascinating metal oxygen clusters of early transition metals, have attracted extensive attention due to their intriguing structures and remarkable potential applications in catalysis, electrochemistry, and medicine etc.^1–15 Among the wide variety of POMs, an interesting family is octamolybdate (Mo₈) which has a variety of structural isomers, such as α-, β-, γ-, δ-, ε-, and ζ-types.^1,16–22 For these complexes, organic functionalization is always an intriguing pursuit for chemists due to a combination of their properties coming from both organic ligands and octamolybdates. It has been confirmed that carboxylate and pyridine ligands are both effective functionalization agents, which can form covalent Mo–O or Mo–N bonds with octamolybdates.^16,17 Therefore, diverse organic-octamolybdate compounds are anticipated based on carboxylate and pyridine organic ligands. However, medicine compounds such as quinolone and its derivatives remain unreported for the direct functionalization of POMs. To date, several medicine–transition-metal complexes modified POMs have been reported.^23,24 As a quinolone derivative, norfloxacin (NF) is a widely used pharmaceutical agent that belongs to third-generation quinolones, which not only possesses relatively high coordination sites and versatile coordination behavior but also shows pharmacological toxicity and fluorescence properties.^25–27 In particular, the fluorescence of norfloxacin is sensitive to pH and thus may be used as an acid–base sensor by monitoring its fluorescence change.²⁸ In view of the above results, the combination of norfloxacin and POMs allows us to obtain functional hybrid materials with pH sensitive properties. Herein, norfloxacin was used as precursor to react with octamolybdate polyoxoanion and led to a new medicine-polyoxometalate compound of (dNF)₂[γ-Mo₈O₂₆(dNF)₂]·10H₂O (1) (dNF, protonated decarboxylic norfloxacin, C₁₅H₁₉FN₃O). It is firstly observed that norfloxacin underwent a decarboxylation process and was directly coordinated to octamolybdate by a carbonyl oxygen atom. The fluorescence properties of 1 were explored and showed interesting sensitivity towards the acidity of the solutions.

In the synthesis of 1, pH value, temperature, and ErCl₃ have key roles in the formation of the final product. The decarboxylation process of the Er³⁺-organic hybrid has been observed by Yang et al.²⁹ The crystals would be in very low yield (0.5%) when the transition metals replace ErCl₃. In the reaction system, it is speculated that the Er³⁺ ions possibly coordinate to a carboxyl group of norfloxacin and favor the coordination between norfloxacin and octamolybdate. Under hydrothermal conditions, the further reaction leads to the decarboxylation process and facilitates the final product of 1. This result indicates that the medicine molecules can be potentially transformed by reaction with POMs and rare earth salts under hydrothermal conditions and thus generate new medicine derivatives and functionalities. Despite the fact that decarboxylation has been observed in some organic compounds during hydrothermal reactions,^30–32 this is however, the first time that decarboxylation has occurred for a medicine molecule under hydrothermal conditions, which opens a new approach to the modification of medicines with new properties.

Single-crystal X-ray diffraction reveals that complex 1 consists of octamolybdate subunits, decarboxylic norfloxacin ligands, and free water molecules (Fig. 1). The octamolybdate subunit in 1 is a γ-type octamolybdate, of which the Mo atoms are all in distorted octahedral environments with Mo–O distances ranging from 1.695(4) to 2.456(4) Å within the reported values.^33–35 Bond valence sum calculations³⁶ showed that the oxidation state of the Mo atoms is located in the range of 5.930–5.960, which is in agreement with the expected value of 6.000. Each octamolybdate polyoxoanion coordinates to two dNF ligands by Mo–O bonds arising from Mo and carbonyl O atoms. It should be noted that such a coordination style is firstly observed among medicine–ligand functionalized POMs. The C–O distance is 1.292(7) Å which is only slightly longer than the normal value for the carbonyl group in norfloxacin. The Mo–O carbonyl bond distance of 2.109(4) Å is similar to the reported values in organic-octamolybdates (2.133(9) Å).³⁷ There also exist isolated dNF molecules located between two neighboring coordinated dNF ligands arising from different [Mo₈O₂₆(dNF)₂]²⁻ units. Weak π⋯π interactions were observed for neighboring dNF ligands with centroid-to-centroid distances in the range of 3.7253(2) Å to 3.9082(2) Å. By such weak interactions, [Mo₈O₂₆(dNF)₂]²⁻ and isolated dNF are linked each other to form 1D chain structures (Fig. 2).

Fig. 1 The coordination mode of octamolybdate and dNF ligands in 1. All the isolated water molecules and H atoms are omitted for clarity.

Fig. 2 1D structure of complex 1. Green polyhedrons represent octamolybdate; the broken lines represent the π⋯π interactions between the neighbor dNF ligands.

The antibacterial activity of 1 was studied using the minimum inhibitory concentration (MIC) and a modified Kirby–Bauer disc diffusion method. The antibacterial activity of 1 decreases compared to the NF precursor (Fig. S1†), in which the MIC values of 1.00 μg mL⁻¹ and 4.20 μg mL⁻¹ against Bacillus subtilis and Escherichia coli for 1 are slightly larger than those of NF of 0.94 μg mL⁻¹ and 1.87 μg mL⁻¹, respectively. This phenomenon is similar to the literature result that decarboxylation facilitates the decrease in antibacterial activity for quinolone medicines.³⁸

The fluorescence properties of 1 and NF have also been investigated. In the solid state, complex 1 is fluorescence silenced which is ascribed to the π⋯π interactions quenching the fluorescence of the dNF ligands. In DMSO solution, as shown in Fig. 3a, the fluorescence intensity of 1 is 6.5 times than the value of NF. The mixture of octamolybdate and NF only leads to a 3.5 times fluorescence enhancement; the stronger fluorescent intensity of 1 also relates to the decarboxylation feature of dNF. This can be explained by the fact that the carboxylate group generally is an electron-withdrawing group that can suppress the fluorescence emission.³⁹ Moreover, in a DMSO/water mixture (v/v = 1/9), the addition of ammonium molybdate (Mo₇) induces the expected fluorescence quenching of dNF (Fig. 3b), the phenomenon of which may be ascribed to a more favorable formation of hydrogen bonds between octamolybdate and dNF in aqueous solution. Here, the fluorescence enhancement of dNF by the introduction of octamolybdate in a non-aqueous solvent is firstly unveiled and opens a new method to modulate the fluorescence of a medicine complex by its inorganic component.

Fig. 3 Fluorescence spectra (Ex = 330 nm) of 1 mmol L⁻¹ 1, 4 mmol L⁻¹ norfloxacin and a mixture of 4 mmol L⁻¹ norfloxacin and 1 mmol L⁻¹ tetrabutylammonium octamolybdate in DMSO solution (a) and 0.4 mmol L⁻¹ norfloxacin and a mixture of 0.4 mmol L⁻¹ norfloxacin and 0.1 mmol L⁻¹ ammonium molybdate in a DMSO/water mixture (v/v = 1/9) (b).

NF has been confirmed a fluorescence sensitive to pH.⁴⁰ As a result of this fact, we investigated the fluorescence properties of 1 in different pH solutions. As shown in Fig. 4, in different pH solutions ranging from 1.0 to 3.5, the fluorescence intensity changed almost linearly with the pH variation, of which the regression equation is y = 142 − 38x (R² = 0.9631). In the pH range of 5.0–9.0, the fluorescence intensity only presented a slight change upon pH increase, whilst the intensity value was almost unchanged in the range of 9.0–12.0, as shown in Fig. 5. To further confirm this speculation, ¹³C NMR spectra were recorded for 1 before and after addition of acid. As shown in Fig. S2,† there are two carbonyl peaks at 166.3 ppm and 175.5 ppm ascribed to bonded and free dNF ligands, respectively. After the addition of HCl acid, the carbonyl peak at 166.3 ppm ascribed to a bonded NF ligand disappeared due to the bond cleavage of the Mo–O_carbonyl bond. Most interestingly, in H₂SO₄ solution (0.5 to 4.0 mol L⁻¹), the fluorescence intensity also linearly varied with the increase in acidity with a regression equation of y = 67 + 9x (R² = 0.9878). Generally, the pH value of the solution can be detected using a pH meter, while this is difficult for the acidity of solutions for pH < 0. The reactivity of 1 towards acidic solutions opens a new route to the fluorescence detection of strong acids by medicine–POM based sensors. In concentrated acidic solution, it should be noted that the fluorescence enhancement may relate to the weak hydrogen-bonds between the polyoxoanion and dNF in a strong protonated environment, which makes the quenching efficiency of polyoxoanion lower than that when in conditions with a higher pH.

Fig. 4 The dependence on different pH (Ex = 330 nm) of the emission intensity (Em = 440 nm) of 1 mmol L⁻¹ 1 in solution (v_DMSO/v_water = 1/9).

Fig. 5 Fluorescence intensity of 1 mmol L⁻¹ 1 in different concentrations of sulphuric acid. Inset shows the linear fit of c(H⁺) versus emission intensity at 440 nm.

In addition to acidity sensitivity, complex 1 can also be considered as an acid–base switch system as its fluorescence can be modulated by the addition of acid and base. As shown in Fig. 6, with the addition of H₂SO₄ at pH = 3.5 to a solution of 1 (H₂SO₄ is controlled as 30 mmol L⁻¹), fluorescence enhancement is observed as ca. 50% increase. When NaOH was added, the fluorescence is quenched for this system (NaOH is controlled as 60 mmol L⁻¹). Considering that that the N of piperazine is protonated in a pH < 4.0 solution, we speculate that the acid induced fluorescence enhancement of 1 comes from the fact that octamolybdate undergoes a transformation to form new polymolybdate species leading to the cleavage of the Mo–O_carbonyl bond. Accordingly, the release of free dNF ligands shows a more intense blue emission as POMs are usually effective quenching agents.⁴¹ A further investigation of the weak interactions between POMs and quinolone medicines will be conducted in due course by our group.

Fig. 6 The fluorescence spectra of 1 (1 mmol L⁻¹) (black), addition of H₂SO₄ (red) and addition of NaOH (blue).

In conclusion, complex 1 was synthesized by a hydrothermal reaction with a decarboxylation process for norfloxacin. The loss of an electron-withdrawing group makes 1 facilitate its fluorescence emission. In a broad range of acidic solutions, even in the pH < 0 range, the fluorescence intensities of 1 almost linearly changed with acidity, by which a solution of 1 can be considered as an acidity fluorescence sensor. Moreover, the enhancing and quenching behavior also makes complex 1 a potential acid–base switch. The successful synthesis of 1 demonstrates a new acidity sensor based on a fluorescent medicine and polyoxometalate anions.

Acknowledgements

We gratefully acknowledge the financial support of the Science and Technology Foundation of Heilongjiang Province Ministry of Education (no. 12541792).

Notes and references

1. M. T. Pope, Heteropoly and Isopoly Oxometalates, Springer, Berlin, 1983.
2. H. T. Evans and M. T. Popev, Inorg. Chem., 1984, 23, 501–504.
3. L. Huang, S.-S. Wang, J.-W. Zhao, L. Cheng and G.-Y. Yang, J. Am. Chem. Soc., 2014, 136, 7637–7642.
4. W. Liu, J. H. Christian, R. Al-Oweini, B. S. Bassil, J. van Tol, M. Atanasov, F. Neese, N. S. Dalal and U. Kortz, Inorg. Chem., 2014, 53, 9274–9283.
5. H. Lv, W. Guo, K. Wu, Z. Chen, J. Bacsa, D. G. Musaev, Y. V. Geletii, S. M. Lauinger, T. Lian and C. L. Hill, J. Am. Chem. Soc., 2014, 136, 14015–14018.
6. G. J. Cao, J. D. Liu, T. T. Zhuang, X. H. Cai and S. T. Zheng, Chem. Commun., 2015, 51, 2048–2051.
7. Q. Tang, Y. Liu, S. Liu, D. He, J. Miao, X. Wang, G. Yang, Z. Shi and Z. Zheng, J. Am. Chem. Soc., 2014, 136, 12444–12449.
8. R. S. Winter, J. M. Cameron and L. Cronin, J. Am. Chem. Soc., 2014, 136, 12753–12761.
9. C. Yvon, A. J. Surman, M. Hutin, J. Alex, B. O. Smith, D.-L. Long and L. Cronin, Angew. Chem., Int. Ed., 2014, 53, 3336–3341.
10. S. Omwoma, C. T. Gore, Y. Ji, C. Hu and Y.-F. Song, Coord. Chem. Rev., 2015, 286, 17–29.
11. X. Xu, X. Gao, T. Lu, X. Liu and X. Wang, J. Mater. Chem. A, 2015, 3, 198–206.
12. X.-L. Hao, Y.-Y. Ma, H.-Y. Zang, Y.-H. Wang, Y.-G. Li and E.-B. Wang, Chem.–Eur. J., 2015, 21, 3778–3784.
13. H. El Moll, W. Zhu, E. Oldfield, L. M. Rodriguez-Albelo, P. Mialane, J. Marrot, N. Vila, I. M. Mbomekallé, E. Rivière, C. Duboc and A. Dolbecq, Inorg. Chem., 2012, 51, 7921–7931.
14. H.-K. Yang, Y.-X. Cheng, M.-M. Su, Y. Xiao, M.-B. Hu, W. Wang and Q. Wang, Bioorg. Med. Chem. Lett., 2013, 23, 1462–1466.
15. B. Hasenknopf, Front. Biosci., 2005, 10, 275–287.
16. R. Xi, B. Wang, K. Isobe, T. Nishioka, K. Toriumi and Y. Ozawa, Inorg. Chem., 1994, 33, 833–836.
17. D. Hagrman, C. Zubeita, D. J. Rose, J. Zubieta and R. C. Haushalter, Angew. Chem., Int. Ed., 1997, 36, 873–876.
18. J.-Q. Xu, R.-Z. Wang, G.-Y. Yang, Y.-H. Xing, D.-M. Li, J.-Q. Xu, W.-M. Bu, L. Ye, Y.-G. Fan, G.-D. Yang, Y. Xing, Y.-H. Lin and H.-Q. Jia, Chem. Commun., 1999, 983–984.
19. L. Luo, H. Lin, L. Li, T. I. Smirnova and P. A. Maggard, Inorg. Chem., 2014, 53, 3464–3470.
20. Y.-Q. Lan, S.-L. Li, X.-L. Wang, K.-Z. Shao, D.-Y. Du, H.-Y. Zang and Z.-M. Su, Inorg. Chem., 2008, 47, 8179–8187.
21. H. Fu, C. Qin, Y. Lu, Z.-M. Zhang, Y.-G. Li, Z.-M. Su, W.-L. Li and E.-B. Wang, Angew. Chem., Int. Ed., 2012, 51, 7985–7989.
22. M. H. Rosnes, C. Yvon, D.-L. Long and L. Cronin, Dalton Trans., 2012, 41, 10071–10079.
23. J. Sha, L. Sun, E. Zheng, H. Qiu, M. Liu, H. Zhao and H. Yuan, J. Coord. Chem., 2013, 66, 602–611.
24. J. Sha, T. Zheng, E. Zhang, H. Qiu, M. Liu, H. Zhao and H. Yuan, J. Coord. Chem., 2013, 66, 977–985.
25. N. Arroyo-Manzanares, J. F. Huertas-Pérez, M. Lombardo-Agüí, L. Gámiz-Gracia and A. M. García-Campaña, Anal. Methods, 2015, 7, 253–259.
26. X. Wei, Z. Zhou, T. Hao, H. Li, J. Dai, L. Gao, X. Zheng, J. Wang and Y. Yan, J. Lumin., 2015, 161, 47–53.
27. Y. Miao, J. Liu, F. Hou and C. Jiang, J. Lumin., 2006, 116, 67–72.
28. P. Bilski, L. J. Martinez, E. B. Koker and C. F. Chignell, Photochem. Photobiol., 1996, 64, 496–500.
29. J. W. Cheng, S. T. Zheng and G. Y. Yang, Inorg. Chem., 2008, 47, 4930–4935.
30. Z.-B. Han, X.-N. Cheng, X.-F. Li and X.-M. Chen, Z. Anorg. Allg. Chem., 2005, 631, 937–942.
31. A. J. Belsky, P. G. Maiella and T. B. Brill, J. Phys. Chem. A, 1999, 103, 4253–4260.
32. P. G. Maiella and T. B. Brill, J. Phys. Chem. A, 1998, 102, 5886–5891.
33. H. Fu, Y. Lu, Z. Wang, C. Liang, Z.-M. Zhang and E. Wang, Dalton Trans., 2012, 41, 4084–4090.
34. W.-Q. Kan, J. Yang, Y.-Y. Liu and J.-F. Ma, Inorg. Chem., 2012, 51, 11266–11278.
35. H. Gao, J. Yu, J. Du, H. Niu, J. Wang, X. Song, W. Zhang and M. Jia, J. Cluster Sci., 2014, 25, 1263–1272.
36. I. D. Brown and D. Altermatt, Acta Crystallogr., Sect. B: Struct. Sci., 1985, 41, 244–247.
37. Q.-Z. Zhang, G.-Q. Shao, G. Chen, H. Shen, G.-H. Lu, R. Ping, P.-F. Xie, Y. Jiang and J. Zhang, J. Chem. Crystallogr., 2007, 37, 369–373.
38. S. T. Nguyen, X. Ding, M. M. Butler, T. F. Tashjian, N. P. Peet and T. L. Bowlin, Bioorg. Med. Chem. Lett., 2011, 21, 5961–5963.
39. X.-F. Zhang, Photochem. Photobiol. Sci., 2010, 9, 1261–1268.
40. K. Takács-Novák, M. Józan, I. Hermecz and G. Szász, Int. J. Pharm., 1992, 79, 89–96.
41. Y. F. Qiu, L. Xu, G. G. Gao, W. J. Wang and F. Y. Li, Inorg. Chim. Acta, 2006, 359, 451–458.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental details, CIF file, FTIR spectrum and tables. CCDC 948997. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra04108b

---