HUANG SHENG-YIN (US)
US20150119374A1 | 2015-04-30 | |||
US20180273406A1 | 2018-09-27 |
HUANG SHENG-YIN, PIERRE VALÉRIE C.: "Achieving Selectivity for Phosphate over Pyrophosphate in Ethanol with Iron(III)-Based Fluorescent Probes", JACS AU, AMERICAN CHEMICAL SOCIETY ; ACS PUBLICATIONS, vol. 2, no. 7, 25 July 2022 (2022-07-25), pages 1604 - 1609, XP093123119, ISSN: 2691-3704, DOI: 10.1021/jacsau.2c00200
CLAIMS We claim: 1. An iron complex comprising a compound of formula I or a salt thereof, wherein Fe is FeII or FeIII; each moiety is independently a pyridinone substituted with one hydroxy or -O-, wherein the pyridinone is optionally substituted with one or more (C1-C6)alkyl, and wherein each dashed bond is independently a single or a double bond; L is a linker, wherein the linker is optionally substituted with -Wa or -C(=O)(C1- C6)alkyl-Xa, and wherein the -C(=O)(C1-C6)alkyl-Xa is optionally substituted with -Wb; Xa is phenyl substituted with hydroxy or -O-; Wa is a linkera group; and Wb is a linkerb group. 2. An iron complex of claim 1 comprising a compound of formula I or a salt thereof, wherein Fe is FeII or FeIII; each moiety is independently a pyridinone substituted with one hydroxy or -O-, wherein the pyridinone is optionally substituted with one or more (C1-C6)alkyl, and wherein each dashed bond is independently a single or a double bond; L is a linker, wherein the linker is optionally substituted with -Wa-Y or -C(=O)(C1- C6)alkyl-Xa, and wherein the -C(=O)(C1-C6)alkyl-Xa is optionally substituted with -Wb-Y; Xa is phenyl substituted with hydroxy or -O-; and Wa is a linkera group; Wb is a linkerb group; and Y is a polymer, hydrogel, membrane, nanoparticle, or material. 3. The iron complex of claim 1, wherein the linkera group and the linkerb group are further optionally substituted with Y, wherein Y is a polymer, hydrogel, membrane, nanoparticle, or material. 4. The iron complex of claim 1, wherein each moiety is independently selected from the group consisting of: wherein each Ra is independently (C1-C6)alkyl. 5. The iron complex of claim 1, wherein each 6. The iron complex of claim 1, wherein each 7. The iron complex of claim 1, wherein each 8. The iron complex of claim 1, wherein each 9. The iron complex of claim 1, wherein each 10. The iron complex of any one of claims 1-9, wherein L is a linker that comprises 5-50 non-hydrogen atoms, wherein the non-hydrogen atoms are selected from halo, C, N, S, and O, wherein the linker is optionally substituted with -Wa or -C(=O)(C1-C6)alkyl-Xa, and wherein the -C(=O)(C1-C6)alkyl-Xa is optionally substituted with -Wb. 11. The iron complex of any one of claims 1-9, wherein L is a linker that comprises 5-15 non-hydrogen atoms, wherein the non-hydrogen atoms are selected from halo, C, N, S, and O, wherein the linker is optionally substituted with -Wa or -C(=O)(C1-C6)alkyl-Xa, and wherein the -C(=O)(C1-C6)alkyl-Xa is optionally substituted with -Wb. 12. The iron complex of any one of claims 1-9, wherein L is a linker that comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(Ra)-, and wherein the chain is optionally substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents independently selected from (C1-C4)alkyl, (C1-C6)alkoxy, oxo (=O), and halo, wherein each Ra is independently H or (C1-C6)alkyl, wherein the linker is optionally substituted with -Wa or -C(=O)(C1-C6)alkyl-Xa, and wherein the -C(=O)(C1-C6)alkyl-Xa is optionally substituted with -Wb. 13. The iron complex of any one of claims 1-9, wherein , wherein the L is optionally substituted with -Wa or -C(=O)(C1-C6)alkyl-Xa, and wherein the - C(=O)(C1-C6)alkyl-Xa is optionally substituted with -Wb and wherein n is 0 or 1. 14. The iron complex of claim 1 comprising a compound of formula Ia’ or a salt thereof, wherein n is 0 or 1, R is H, -Wa, or -C(=O)(C1-C6)alkyl-Xa, and wherein the -C(=O)(C1- C6)alkyl-Xa is optionally substituted with -Wb. 15. The iron complex of claim 14, wherein R is H. 16. The iron complex of claim 14, wherein R is -Wa. 17. The iron complex of claim 14, wherein R is -C(=O)(C1-C6)alkyl-Xa , wherein the - C(=O)(C1-C6)alkyl-Xa is optionally substituted with -Wb. 18. The iron complex of claim 1 comprising a compound of formula Ib’ or a salt thereof, wherein n is 0 or 1; R1 is H or -Wb. 19. The iron complex of any one of claims 1-14 or 16-18, wherein each Wa and Wb independently comprises 2-50 non-hydrogen atoms, wherein the non-hydrogen atoms are selected from halo, C, N, S, and O. 20. The iron complex of any one of claims 1-14 or 16-18, wherein each Wa and Wb independently comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(Ra)-, and wherein the chain is optionally substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents independently selected from oxo (C=O), (C1- C4)alkyl, (C1-C6)alkoxy, hydroxy, and halo, wherein each Ra is independently H or (C1-C6)alkyl. 21. The iron complex of any one of claims 1-14 or 16-18, wherein each Wa and Wb independently comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(Ra)-, and wherein the chain is optionally substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents independently selected from oxo (C=O), (C1-C4)alkyl, (C1-C6)alkoxy, hydroxy, and halo, wherein each Ra is independently H or (C1- C6)alkyl, wherein the chain is substituted with one or more reactive groups. 22. The iron complex of any one of claims 1-14 or 16-18, wherein each Wa and Wb independently comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 10 carbon atoms wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(Ra)-, and wherein the chain is optionally substituted with one or more (e.g.1, 2, 3, 4, 5 or more) substituents independently selected from oxo (C=O), (C1-C4)alkyl, (C1-C6)alkoxy, hydroxy, and halo, wherein each Ra is independently H or (C1- C6)alkyl, wherein the chain is substituted with one or more reactive groups. 23. The iron complex of claim 21 or 22, wherein each reactive group is independently an amine, thiol, hydroxy, amide or ester. 24. The iron complex of any one of claims 1-14 or 16-18, wherein ; R is H or (C1-C6)alkyl; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 25. The iron complex of claim 1, wherein the compound of formula I is: or a salt thereof. 26. A material or device comprising one or more an iron complexes or salts thereof as described in any one of claims 1-25, 27. The material or device of claim 26, wherein the material or device is attached to linker Wa or Wb. 28. The material or device of claim 26 or 27, comprising one or more iron complexes selected from or a salt thereof. 29. The iron complex or salt thereof of any one of claims 26-28, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 30. The iron complex or salt thereof of claim 2, wherein the compound of formula I is or a salt thereof. 31. The iron complex of claim 1, wherein the compound of formula I is: or a salt thereof. 32. The iron complex of any one of claims 1-31 further comprising a weak binding ligand. 33. The iron complex of claim 32, wherein the weak binding ligand is fluorescein. 34. A method to detect inorganic phosphate comprising contacting the phosphate with an iron complex as described in any one of claims 1-33. 35. The method of claim 34 wherein the phosphate is selectively detected in the presence of other anions. 36 The method of claim 35, wherein the other anions are selected from the group consisting of carbonate, nitrate, sulfate, halides, arsenate and pyrophosphate. 37. The method of any one of claims 34-36, wherein the phosphate is contacted with the iron complex as a liquid sample at about neutral pH. 38. The method of claim 37, wherein the liquid sample is sample obtained from a body of water. 39. The method of claim 37 or 38, where the liquid sample is a eutrophic sample. 40. The method of any one of claims 34-39, wherein the phosphate is detected by fluorescence sensing by an indicator displacement assay. 41. A method to remove inorganic phosphate from an aqueous mixture or solution comprising contacting the aqueous mixture or solution with an iron complex as described in any one of claims 1-33. 42. The method of claim 41, wherein the aqueous mixture or solution is waste water. 43. A method to treat hyperphosphatemia in a mammal in need thereof comprising contacting the blood of the mammal in need thereof, with an iron complex as described in any one of claims 1-33. 44. The method of claim 43, wherein the mammal has chronic kidney disease. 45. A ligand of formula II wherein: each moiety is independently a pyridinone substituted with one hydroxy or -O-, wherein the pyridinone is optionally substituted with one or more (C1-C6); L is a linker, wherein the linker is optionally substituted with -Wa-Y or -C(=O)(C1-C6)alkyl-Xa, and wherein the -C(=O)(C1-C6)alkyl-Xa is optionally substituted with - Wb-Y; Xa is phenyl substituted with hydroxy or -O-; Wa is a linkera group; Wb is a linkerb group; and Y is a polymer, hydrogel, membrane, nanoparticle, or material. 46. A ligand of formula II II each moiety is independently a pyridinone substituted with one hydroxy or -O-, wherein the pyridinone is optionally substituted with one or more (C1-C6)alkyl; L is a linker, wherein the linker is optionally substituted with -Wa or -C(=O)(C1- C6)alkyl-Xa, and wherein the -C(=O)(C1-C6)alkyl-Xa is optionally substituted with -Wb; Xa is phenyl substituted with hydroxy or -O-; Wa is a linkera group; and Wb is a linkerb group. 47. The ligand of claim 45 or 46, wherein A, L, Xa, Wa, Wb and Y are as defined in any one of claims 1-33. 48. The compound or salt thereof of formula I as defined in any one of claims 1-33, wherein the iron (Fe (FeII or FeIII is absent)) is absent. |
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment , wherein the L is optionally substituted with -W a or -C(=O)(C 1 -C 6 )alkyl-X a , and wherein the -C(=O)(C 1 -C 6 )alkyl-X a is optionally substituted with -W b and wherein n is 0 or 1. In one embodiment the compound of formula I is a compound of formula Ia’ or a salt thereof, wherein n is 0 or 1, R is H, -W a , or -C(=O)(C1-C6)alkyl-X a , and wherein the -C(=O)(C1- C 6 )alkyl-X a is optionally substituted with -W b . In one embodiment the compound of formula I is a compound of formula Ib’
or a salt thereof, wherein n is 0 or 1; R 1 is H or -W b . In one embodiment the compound of formula I is:
. In one embodiment the compound of formula I is: . One embodiment provides a material or device comprising one or more iron complexes or salts thereof as described herein. Ine one embodiment the material or device is attached to the one or more iron complexes or salts thereof at the linker W a or W b . One embodiment provides a material or device comprising one or more iron complexes selected from
or a salt thereof, wherein the material or device is bonded to W a or W b as shown by the wavy line. In one embodiment n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. One embodiment provides a ligand or salt thereof of formula II II wherein: each moiety is independently a pyridinone substituted with one hydroxy or -O- wherein the pyridinone is optionally substituted with one or more (C1-C6)alkyl, and wherein each dashed bond is independently a single or a double bond; L is a linker, wherein the linker is optionally substituted with -W a -Y or -C(=O)(C1-C6)alkyl-X a , and wherein the -C(=O)(C1-C6)alkyl-X a is optionally substituted with - W b -Y; X a is phenyl substituted with hydroxy or -O-; W a is a linker a group; W b is a linker b group; and Y is a polymer, hydrogel, membrane, nanoparticle, or material. One embodiment provides the ligand of formula II II wherein: each moiety is independently a pyridinone substituted with one hydroxy or -O-, wherein the pyridinone is optionally substituted with one or more (C1-C6)alkyl, and wherein each dashed bond is independently a single or a double bond; L is a linker, wherein the linker is optionally substituted with -W a or -C(=O)(C 1 - C6)alkyl-X a , and wherein the -C(=O)(C1-C6)alkyl-X a is optionally substituted with -W b ; X a is phenyl substituted with hydroxy or -O-; W a is a linker a group; and W b is a linker b group. One embodiment provides the ligand of formula II, wherein A, L, X a, W a , W b and Y are as defined in any embodiment or claim provided herein. One embodiment provides the compound as described herein that does not include the iron atom. One embodiment provides an iron complex comprising a compound of formula Ic or a salt thereof, wherein Fe is Fe II or Fe III or a combination thereof; X 1 is C or N; X 2 together with oxygen to which it is attached is N-O, C-O, C=O; X 3 together with oxygen to which it is attached is N-O, C-O, C=O; X 4 is C or NR a ; X 5 is C or NR a ; wherein the ring formed by X 1 , X 2 , X3, X 4 , X 5 and the carbon is a pyridinone, wherein the pyrdinone is substituted with one hydroxy or -O-, wherein the pyridinone is optionally substituted with one or more (C 1 -C 6 )alkyl; each R a is independently (C 1 -C 6 )alkyl. L is a linker, wherein the linker is optionally substituted with -W a or -C(=O)(C1- C6)alkyl-X a , and wherein the -C(=O)(C1-C6)alkyl-X a is optionally substituted with -W b ; X a is phenyl substituted with hydroxy or -O-; W a is a linker a group; and W b is a linker b group. One embodiment provides an iron complex comprising a compound of formula Id Id or a salt thereof. One embodiment provides an iron complex as described herein further comprising a weak binding ligand. In one embodiment the weak binding ligand is fluorescein. One embodiment provides a method to detect inorganic phosphate comprising contacting the phosphate with an iron complex as described herein. In one embodiment the phosphate is selectively detected in the presence of other anions. In one embodiment the anions are selected from the group consisting of carbonate, nitrate, sulfate, halides, arsenate and pyrophosphate. Ine one embodiment the phosphate is contacted with the iron complex as a liquid sample at about neutral pH. In one embodiment the liquid sample is obtained from a body of water. In one embodiment the liquid sample is a eutrophic sample. In one embodiment the phosphate is detected by fluorescence sensing by an indicator displacement assay. One embodiment provides a method to remove inorganic phosphate from an aqueous mixture or solution comprising contacting the aqueous mixture or solution with an iron complex as described herein. One embodiment provides a method to sequester or remove inorganic phosphate from an aqueous mixture or solution comprising contacting the aqueous mixture or solution with an iron complex as described herein. One embodiment provides a method to remove inorganic phosphate from an aqueous mixture or solution comprising contacting the aqueous mixture or solution with an iron complex as described herein, under conditions wherein the phosphate binds to the iron complex and is partially or completely removed from the mixture or solution. One embodiment provides a method to sequester or remove inorganic phosphate from an aqueous mixture or solution comprising contacting the aqueous mixture or solution with an iron complex as described herein, under conditions wherein the phosphate binds to the iron complex and is partially or completely removed from the mixture or solution.. The invention will now be illustrated by the following non-limiting example. Example 1. Experimental Section Unless otherwise stated, all chemicals were purchased from commercial suppliers and used without further purification. Deuterated solvents were obtained from Cambridge Isotope Laboratories (Tewskbury, MA, USA). Distilled water was further purified by a Millipore Simplicity UV system (resistivity 18×10 6 Ω). All organic extracts were dried over anhydrous MgSO4 (s). NaF, NaCl, NaBr, NaI, Na2SO4, NaNO3, NaHCO3, NaOAc, Na4P2O7, and Na 2 HAsO 4 ·7H 2 O were used for anion screen studies. Flash chromatography was performed on Merck Silica Gel. Modified silica gel was prepared by heating the silica gel in 37% HCl (aq) at 50℃ for 6 h, further washing it with deionized water until the pH of the filtrate was neutral and drying it under reduced pressure at 100℃. The collected silica gel was subsequently suspended in toluene with 1% (v/v) hexadecyltrimethoxysilane. The mixture was stirred at 100°C for 6 h, after which the mixture was filtered, rinsed with toluene and ethyl acetate, and dried under reduced pressure at 100°C. 1 H NMR and 13 C NMR spectra were recorded at room temperature on a Bruker Advance III 400 at 400 MHz and 100 MHz, respectively, or a Bruker Advance III AV 500 at 500 MHz and 125 MHz, respectively, at the LeClaire-Dow instrumentation facility of the Department of Chemistry of the University of Minnesota. The residual solvent peaks were used as internal references. Data for 1 H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet, t, triplet; q, quartet; br, broad; m, multiplet), coupling constant (Hz), integration. Data for 13 C NMR are recorded as follows: chemical shift (δ, ppm). Low resolution (LR) and high resolution (HR) electrospray spray ionization time-of-flight mass spectrometry (ESI/TOF-MS) were recorded on a Bruker BioTOF I at the LeClaire-Dow instrumentation facility of the Department of Chemistry of the University of Minnesota. UV- visible spectra were recorded on a Varian Cary 100 Bio Spectrophotometer. Data was collected over the range of 200 – 800 nm. Luminescence data was acquired on a Varian Cary Eclipse Fluorescence Spectrophotometer using a quartz cell with a path length of 1 cm and chamber volume 400 ^L. Sample solutions were allowed to equilibrate for 5 min before measurement of their luminescence spectra, as initial studies demonstrated that this time was sufficient to achieve thermodynamic equilibrium (Figure 17 and Figure 18). All fluorescent titration data were acquired at room temperature (T = 25 ℃ ). Every data point was measured in triplicate from three independently prepared samples. For fluorescent titrations or anion selectivity studies, 5 mM of anions were prepared in water and pH adjusted to 7 using 0.1 N HCl or 0.1 N NaOH. Wet ethanol denotes the water content is ≤ 10 (v/v%) in ethanol. Luminescence data were processed with Scilab 6.0.2 and QtiPlot 0.9.8.9 software. All pH measurements were performed using Thermo Scientific Ag/AgCl refillable probe and a Thermo Orion 3 Benchtop pH meter. High-performance liquid chromatography (HPLC) data was collected on a Varian Prostar Model 210, coupled with an Agilent ZORBAX Eclipse XDB-C18 column, and a Varian ProStar 335 diode array detector. Unless specified otherwise HPLC measurements were performed at a flow rate 1.0 mL min −1 with the following elution condition: 15% CH 3 CN/85% water from 0 to 10 minutes, followed with a linear gradient to 85% CH 3 CN/15% water from 10 to 23 minutes, 85% CH3CN/15% water from 23 to 45 minutes. Synthesis 4-Nitrophenyl 1-(benzyloxy)-6-oxo-1,6-dihydropyridine-2-carboxylate (3). The p- nitrophenol activated ester was prepared in reference to a similar procedure for the preparation of N-hydroxysuccinimidyl ester of the podant (F. Guérard, M. Beyler, Y.-S. Lee, R. Tripier, J.-F. Gestin, M. W. Brechbiel, Dalton Trans.2017, 46, 4749–4758). HOPO(Bn)-OH (1000. mg, 4.080 mmol) was suspended in anhydrous methylene chloride (10 mL) under N2 atmosphere, followed by the injection of oxalyl chloride (400. ^L, 4.90 mmol) and one drop of DMF. The reaction was let stir for 1 hr at room temperature before the removal of solvent, HCl, and excess oxalyl chloride by high vacuum with liquid N 2 trap. Under N 2 atmosphere, the residue was dissolved in 10 mL anhydrous methylene chloride. After p-nitrophenol (568 mg, 4.08 mmol) was added to the solution, the mixture was cooled by ice bath, and NEt3 (900 ^L, 6.10 mmol) was injected slowly to the mixture. The mixture was then warmed up to room temperature for 6 hr, after which it was washed with 10% citric acid solution, 10% sodium bicarbonate solution, dried over anhydrous MgSO 4 (s), and concentrated under vacuum to a viscous liquid. This crude product was purified by flash chromatography over silica eluting with 60% EtOAc / 20% Hex to yield white solid 3 (1.363 g, 91 %). 1 H NMR (400 MHz, CDCl 3 ): ^ 8.29 (d, J = 9 Hz, 2H), 7.49 (d, J = 6 Hz, 2H), 7.41-7.26 (m, 6H), 6.94 (d, J = 9 Hz, 1H), 6.79 (d, J = 7 Hz, 1H), 5.42 (s, 2H). 13 C NMR (100 MHz, CDCl 3 ): ^ 158.6, 157.2, 154.4, 145.8, 137.1, 136.9, 133.3, 130.2, 129.4, 128.6, 127.6, 125.3, 122.2, 109.4, 78.8. ESI-HRMS: m/z = 389.0755 ([M+Na] + ), (Calcd. 389.0744). N,N'-(Azanediylbis(ethane-2,1-diyl))bis(1-(benzyloxy)-6-oxo- 1,6-dihydropyridine-2- carboxamide) (4). p-nitrophenol activated ester 3 (808 mg, 2.207 mmol) was dissolved in 20 mL methylene chloride, followed by slow injection of diethylenetriamine (119 ^L, 1.10 mmol) and NEt3 (300. ^L, 2.21 mmol). The reaction was stirred at room temperature for 1 hr. The mixture was washed with 20 mL of 1N NaOH solution, dried over anhydrous MgSO4 (s), and concentrated under vacuum to a viscous liquid. This crude product was purified by flash chromatography over silica eluting with 12% MeOH / 88% CH 2 Cl 2 to yield foaming liquid 4 (1.045 g, 85 %). 1 H NMR (400 MHz, CDCl 3 ): ^ 7.59 (br, 2H), 7.35-7.22 (m, 10H), 7.14 (dd, J 1 = 9 Hz, J2 = 7 Hz, 2H), 6.36 (d, J = 9 Hz, 2H), 6.21 (d, J = 7 Hz, 2H), 5.18 (s, 4H), 3.14 (d, J = 10 Hz, 4H), 2.51-2.48 (m, 4H), 1.62 (br,1H). 13 C NMR (100 MHz, CDCl 3 ): ^ 160.4, 158.3, 143.0, 138.3, 133.3, 129.6, 129.0, 128.3, 123.0, 105.6, 78.9, 47.1, 39.3. ESI-HRMS: m/z = 580.2156 ([M+Na] + ), (Calcd.580.2167). N,N'-(Azanediylbis(ethane-2,1-diyl))bis(1-hydroxy-6-oxo-1,6- dihydropyridine-2- carboxamide) HBr (5). The protected ligand 4 (200. mg, 0.359 mmol) was dissolved in 1 mL of glacial acetic acid, and 1 mL of 30% HBr was added to the reaction mixture. After 6 hr, acetic acid and HBr were removed under high vacuum to yield a foaming liquid. This crude product was purified by flash chromatography over modified silica eluting with 0% MeOH / 100% H 2 O gradient to 5% MeOH / 95% H 2 O to yield white foaming liquid 5 (150 mg, 91%). 1 H NMR (400 MHz, CF3COOD): ^ 7.80 (t, J = 8 Hz, 2H), 7.52 (d, J = 8 Hz, 2H), 7.30 (d, J = 9 Hz, 2H), 4.00 (br, 4H), 3.65 (br, 4H). 13 C NMR (100 MHz, CF3COOD): ^ 165.4, 160.1, 141.4, 138.0, 121.9, 118.6, 51.6, 40.0. ESI-HRMS: m/z = 378.1310 ([M-Br] + ), (Calcd.378.1408). Fe III -HOPO-fluo (1). Ligand 5 (5.0 mg, 0.011 mmol) and fluorescein (3.6 mg, 0.011 mmol) was suspended in anhydrous EtOH (10 mL), followed by injection of 1N NaOH (22 ^L, 0.022 mmol).0.1 N ethanolic FeBr3 (110 ^L, 0.011 mmol) was then added to the reaction mixture. The purity and identity of Fe III -HOPO-fluo formed in situ were characterized by HPLC and ESI-HRMS. The solution was used without further purification. ESI-HRMS: m/z = 763.1138 ([M-Br] + ), (Calcd.763.1208). 3-(2-(Benzyloxy)phenyl)propanoic acid (6). The benzyl protected side arm 6 was synthesized according to the reported procedure [2] and characterized by NMR and ESI-HRMS. 1 H NMR (400 MHz, CDCl 3 ): ^ 11.05 (br, 1H), 7.46-7.32 (m, 5H), 7.26-7.19 (m, 2H), 6.94-6.90 (m, 2H), 5.12 (s, 2H), 3.04 (t, J = 8 Hz, 2H), 2.72 (t, J = 8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ): ^ 179.6, 156.5, 137.2, 130.1, 128.8, 128.6, 127.8, 127.7, 127.0, 120.8, 111.6, 69.8, 34.0, 25.9. ESI-HRMS: m/z = 279.1009 ([M+Na] + ), (Calcd.279.0992). 1-(Benzyloxy)-N-(2-(N-(2-(1-(benzyloxy)-6-oxo-1,6-dihydropyr idine-2- carboxamido)ethyl)-3-(2-(benzyloxy)phenyl)propanamido)ethyl) -6-oxo-1,6-dihydropyridine-2- carboxamide (7). The protected side arm 6 (316 mg, 1.23 mmol) was suspended in anhydrous methylene chloride (10 mL) under N2 atmosphere, followed by the injection of oxalyl chloride (0.1 mL, 1.4 mmol) and one drop of DMF. The reaction was let stir for 1 hr at room temperature before the removal of solvent, HCl, and excess oxalyl chloride by high vacuum with liquid N2 trap. Under N 2 atmosphere, the residue was dissolved in 10 mL anhydrous methylene chloride and cooled with ice bath. The protected ligand 4 (687 mg, 1.23 mmol) was dissolved in anhydrous methylene chloride (5 mL) and slowly injected to the cooled reaction mixture. To the mixture was then injected NEt3 (344 ^L, 2.47 mmol). The mixture was then warmed up to room temperature for 1 hr, after which it was washed with 10% citric acid solution, dried over anhydrous MgSO 4 (s), and concentrated under vacuum to a viscous liquid. This crude product was purified by flash chromatography over silica eluting with 4% MeOH / 96% CH 2 Cl 2 to yield white foaming liquid 7 (805 mg, 82%). 1 H NMR (400 MHz, CDCl3): ^ 7.48-7.46 (m, 2H), 7.41- 7.36 (m, 5H), 7.34-7.27 (m, 9 H), 7.25-7.21 (m, 2H),7.13-7.09 (m, 2H), 6.94 (br, 1H), 6.89-6.82 (m, 3H), 6.68 (dd, J 1 = 1 Hz, J 2 = 8 Hz, 2H), 6.24 (t, J = 2 Hz, 1H), 6.23 (t, J = 2 Hz, 1H), 5.32 (s, 2H), 5.24 (s, 2H), 5.02 (s, 2H), 3.31 (br, 4H), 3.06 (br, 4H), 2.88 (t, J = 7 Hz, 2H), 2.48 (t, J = 8 Hz, 2H). 13 C NMR (100 MHz, CDCl3): ^ 174.3, 160.7, 160.6, 158.5, 158.4, 156.5, 142.8, 142.2, 138.0, 137.9, 137.0, 133.5, 133.1, 130.3, 130.1, 129.5, 129.1, 128.60, 128.55, 128.50, 128.0, 127.7, 127.3, 124.1, 120.8, 111.6, 105.9, 105.2, 79.3, 79.0, 69.9, 47.40, 45.7, 39.3, 38.7, 32.8, 26.9. ESI-HRMS: m/z = 818.3181 ([M+Na] + ), (Calcd.818.3160). 1-Hydroxy-N-(2-(N-(2-(1-hydroxy-6-oxo-1,6-dihydropyridine-2- carboxamido)ethyl)-3- (2-hydroxyphenyl)propanamido)ethyl)-6-oxo-1,6-dihydropyridin e-2-carboxamide (8). The protected ligand 7 (450. mg, 0.566 mmol) was dissolved in 1 mL of glacial acetic acid, and 1 mL of 30% HBr was added to the reaction mixture. After 6 hr, acetic acid and HBr were removed under high vacuum to yield a foaming liquid. This crude product was purified by flash chromatography over modified silica eluting with 0% MeOH / 100% H 2 O gradient to 5% MeOH / 95% H2O to yield white foaming liquid 8 (270 mg, 91%). 1 H NMR (500 MHz, CD3OD): ^ 7.48-7.42 (m, 2H), 7.04 (d, J = 7 Hz, 1H), 6.97 (dd, J 1 = 1 Hz, J 2 = 8 Hz, 2H), 6.75-6.68 (m, 4H), 6.61 (dd, J1 = 1 Hz, J2 = 7 Hz, 1H), 6.56 (dd, J1 = 1 Hz, J2 = 7 Hz, 1H), 3.65-3.61 (m, 4H), 3.56- 3.54 (m, 4H), 2.88 (t, J = 7 Hz, 2H), 2.75 (t, J = 8 Hz, 2H). 13 C NMR (125 MHz, CD 3 OD): ^ 176.5, 162.8, 162.7, 160.2, 160.1, 156.5, 142.0, 141.7, 139.0, 138.8, 131.5, 128.7, 120.94, 120.85, 116.4, 108.7, 108.5, 48.3, 46.3, 39.4, 39.0, 34.7, 27.6. ESI-HRMS: m/z = 524.1775 ([M- H]-), (Calcd.524.1776). Fe III -HOPO-PhO-fluo (2). Ligand 8 (5.0 mg, 9.5 ^mol) and fluorescein (3.6 mg, 9.5 ^mol) was suspended in anhydrous EtOH (10 mL), followed by injection of 1N NaOH (29 ^L, 29 ^mol).0.1 N ethanolic FeBr 3 (95 ^L, 9.5 ^mol) was then added to the reaction mixture. The purity and identity of Fe III -HOPO-PhO-fluo formed in situ were characterized by HPLC and ESI-HRMS. The solution was used without further purification. ESI-HRMS: m/z = 911.1830 ([M+3H] + ), (Calcd.911.1733). Data Fitting Data fitting of Fe III -complexes + Pi uses the following equations: where H denotes the host (Fe III -complex-fluo), G the guest (Pi), and HG the adduct. Equilibrium constants K is defined as: The luminescence intensity increase can be described as the following: 2 F = integrated fluorescence, F0 = initial integrated fluorescence, Δ F max = F ∞ - F 0 . Non-linear fitting was performed using QtiPlot 1.0.0 software. Detection limits were calculated according to , where ^^ is the standard deviation of the fitting. The fitting results are shown in Figure 38 and Table S1 Discussion The receptors Fe III -HOPO-fluo and Fe III -HOPO-PhO-fluo were synthesized according to Schemes 1 and 2, respectively. The p-nitrophenol activated ester of the benzyl-protected HOPO podand 3, previously synthesized following literature precedence, 39 selectively acylate the primary amino groups of the triamine backbone to yield the protected ligand 4. Deprotection under strong acidic conditions yields the final ligand 5, which was further metallated with Fe III in the presence of fluorescein to give the final receptor Fe III -HOPO-fluo. Scheme 1 Synthesis of FeIII-HOPO-PhO-fluor a Fe III -HOPO-PhO-fluo employs a pentadentate ligand whose phenolate moiety occupies one more coordination site of the Fe III center. Activation of the benzyl-protected phenol podand 6, previously synthesized according to literature reports, 40 with oxalyl chloride enabled coupling to the central secondary amine of 4, thereby yielding the protected ligand 7. Deprotection under strong acidic conditions yielded the final ligand 8 that was further metallated with Fe III in the presence of fluorescein to give the final receptor Fe III -HOPO-PhO-fluo, 2. In both syntheses, formation and purity of the ternary complexes 1 and 2 was confirmed by HPLC and ESI-MS (Figures 5, 7, 8, and 10). No ^-oxo diiron dimer were detected, confirming that coordination of the fluorescein ligand is sufficient to protect the Fe III center and prevent the formation of bimetallic species. In contrast, in the absence of fluorescein, the ^-oxo diiron dimer is the predominant species observed by MS. The significant line broadening observed in the 1 H NMR of the ternary complexes in solution (Figures 6 and 9), which is typical of paramagnetic Fe(III) species, further confirmed coordination of fluorescein to the receptors 1 and 2. Both Fe III ·fluorescein complexes were stable as solids and in ethanol for weeks; both can tolerate up to 10 vol% water with pH adjusted to 7 without significant fluorescein dissociation (< 1%) in ethanol. Direct coordination of phosphate to the iron centers of the receptors concomitant with displacement of the fluorescein moiety upon addition of the oxyanion was first confirmed from attenuated total reflection-infrared (ATR-IR) spectroscopic analysis of the precipitate obtained from Fe III -HOPO-fluo+Pi and Fe III -HOPO-PhO-fluo+Pi. The iron complex Fe III -HOPO-Pi displays the characteristic ^(Fe-O) vibrations at 571 and 461 cm -1 , ^(P-O) bands at 1088, 1067, 968 cm -1 and ^ (O-P-O) bands at (541) cm -1 (Figure 2A). 41–44 Each of those bands was also observed for the Fe III -HOPO-PhO-Pi adduct (Figure 11). These observations are in agreement with the formation of the postulated ternary complexes. Formation of a Fe III L·Pi ternary complex was also supported by NMR spectroscopy. The 31 P NMR spectrum of Fe III -HOPO-Pi is nearly featureless (Figure 12), an observation that is attributed to the shortened transverse relaxation times, T2, of the 31 P nucleus by the strongly paramagnetic Fe III . As is apparent in Figure 2B, when referenced to an external standard of H 3 PO 4 , in a titration monitored by NMR, the 31 P signal of phosphate progressively shifts downfield from 1.61 to 4.72 ppm upon gradual addition of Fe III -HOPO-fluo (1). This shift is accompanied by a significant line broadening corresponding to a decrease in T 2 of the phosphorus nuclei from 0.11 s (no Fe III -HOPO-fluo) to 1.95 ms (1 equivalent of Fe III -HOPO- fluo). Both of those observations are attributable to coordination of orthophosphate to the strongly paramagnetic Fe III center. 45,46 Of note, the presence of a single peak in the 31 P also suggests the presence of a rapid equilibrium between bound and free phosphate. Fe III -HOPO- PhO-fluo (2), which employs a pentadentate ligand, displays similar behavior with the coordination of phosphate to the Fe III center confirmed from both the ATR-IR and the 31 P NMR spectra (Figures 11 and 12, respectively). Unfortunately, further attempts to characterize the ternary phosphate complexes by mass spectrometry were unsuccessful due to the their low solubility and the known ability of phosphate to suppress ionization. 47,48 The indicator displacement assays (IDA) was evaluated by both UV-visible and fluorescence spectroscopy. A 20-fold turn-on fluorescence was observed upon gradual addition of 1 equivalent of orthophosphate (Figure 3A). The fluorescence titrations (Figure 3 and Figure 19) of both receptors were best fitted to a 1:1 binding model from which the equilibrium constants were derived (Table 1). This 1:1 stoichiometry was determined first by evaluating the fit of the titrations and subsequently confirmed by Job’s plots (Figures 15 and 16 for Fe III - HOPO-fluo and Fe III -HOPO-PhO-fluo, respectively). Interestingly, the use of a tetradentate ligand in Fe III -HOPO-fluo does not appear to favor coordination of two phosphate anions to the metal center. The two receptors display similar turn-on response (20-fold at 1 equivalent) and similar equilibrium constants for phosphate: 8.8 × 10 5 M -1 and 1.1 × 10 6 M -1 for Fe III -HOPO- fluo and Fe III -HOPO-PhO-fluo respectively. This similarity in both turn-on response and apparent equilibrium constants could be attributed to the comparable core structure of both receptors. Interestingly, the extra phenolate podand of 2 does not appear to affect displacement of the fluorescein moiety by phosphate. A likely coordinated solvent molecule appears to have similar effect. The limit of detection (LOD) of phosphate by the two Fe III receptors, commonly estimated as three times the standard deviation of measurement (3 ^^), are 3.5 ^M and 4.1 ^M for Fe III -HOPO-fluo (1) and Fe III -HOPO-PhO-fluo (2), respectively (Table S1). Although not quite as sensitive as prior Eu III probes, 21,22 these iron receptors are sensitive enough to detect problematic phosphate levels in eutrophic samples (2-10 ^M). 49,50 Table 1. Apparent equilibrium constants of Fe III -HOPO-fluo (1) and Fe III -HOPO-PhO-fluo (2) with orthophosphate. The selectivity of the two iron receptors for phosphate over competing anions commonly found in environmental samples was also evaluated by fluorescence spectroscopy. As shown in the white bars of Figure 4, the fluorescence intensity of both probes is not affected by the addition of 1 equivalent of common competing anions including halides, sulfate, and nitrate. Subsequent addition of 1 equivalent of phosphate restores the luminescence of the indicator (Figure 4, grey bars) further indicating that these competing anions do not interfere with detection of phosphate. Interestingly, Fe III -HOPO-fluo is more selective over bicarbonate and acetate than Fe III -HOPO-PhO-fluo. A more sterically hindered recognition site therefore does not appear to generate higher selectivity for the targeted anion. Uniquely, and importantly, both Fe III -HOPO-fluo (1) and Fe III -HOPO-PhO-fluo (2) are selective for phosphate over pyrophosphate. Whereas numerous probes selective for pyrophosphate over phosphates have been described in the literature, 39–41 it is believed that complexes 1 and 2 are unique in their reverse selectivity for phosphate over pyrophosphate. This selectivity likely stems from the preferred bidentate binding mode of pyrophosphate and likely steric hindrance at the coordination site. 51,52 Since only one displaceable fluorescein is present, bidentate binding is disfavored. The slightly softer anion - arsenate, also does not displace fluorescein despite its structurally similarity to phosphate. This is an unusual selectivity given as most metal probe for phosphate also respond to arsenate. 7 As such, these fluorescent iron(III) probes offer a distinctive ability to rapidly monitor the level of the most important phosphorus species causing nutrient pollution in surface water: phosphate. Summary Herein is described non-heme iron(III) complexes, including Fe III -HOPO-fluo and Fe III - HOPO-PhO-fluo, for selective recognition of inorganic phosphate. This is demonstrated via indicator displacement assay. The open coordination sites were sufficiently protected by weakly coordinating fluorescein to prevent dimerization in aerated solutions. Coordination of inorganic phosphate concomitant with displacement of the fluorescein moiety increases the emission of the latter by 20-fold. Uniquely, these probes distinguish themselves from other receptors that function by direct metal coordination in that they are highly selective for phosphate over pyrophosphate. They are also highly selective over common competing endogenous anions such as carbonate, nitrate, sulfate, halides and, unusually, arsenate. The limit of detection of the iron(III) receptors, 3.5 and 4.1 ^M for Fe III -HOPO-fluo and Fe III -HOPO-PhO-fluo, respectively, enables detection of phosphate typical of eutrophic water samples. On this basis, the two iron(III) probes enable rapid and facile detection of phosphate in eutrophic samples. 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