CA2246204A1 - Bipodal ligand-metal ion chelates - Google Patents
Bipodal ligand-metal ion chelates Download PDFInfo
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- CA2246204A1 CA2246204A1 CA 2246204 CA2246204A CA2246204A1 CA 2246204 A1 CA2246204 A1 CA 2246204A1 CA 2246204 CA2246204 CA 2246204 CA 2246204 A CA2246204 A CA 2246204A CA 2246204 A1 CA2246204 A1 CA 2246204A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic System
- C07F13/005—Compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
Abstract
The invention relates to complexes comprising a metal ion and chelating ligands which incorporate a bipodal backbone. More particularly, the invention pertains to bipodal ligand bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (H5xuta) which forms novel coordination compounds with a variety of metal ions, particularly, but not exclusively, trivalent metal ions and lanthanide metal ions, which are useful in nuclear medicine. The process comprises complexing Tc or Re or any one of the group 13 metals, Al, Ga and In, and any one of the rare earths, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, with the H5xuta bipodal ligand.
Description
BIPODAL LIGAND-METAL ION CHELATES
FIELD OF THE INVENTION
The invention relates to novel complexes comprising a metal ion and a ligand which incorporates a bipodal backbone. More particularly, the invention pertains to a bipodal ligand bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (HSxuta) which forms novel coordination compounds with a variety of metal ions, particularly, but not exclusively, trivalent metal ions and lanthanide metal ions, which are useful in nuclear medicine.
BACKGROUND OF THE INVENTION
In recent years, vigorous research activity has been conducted to identify and synthesize suitable chelating agents for metal ions and particularly trivalent metal ions such as the group 13 metals and the lanthanides, for use in nuclear medicine. This is because of the deleterious effects of these metals (e.g.
concern over aluminum neurotoxicity) in unprotected form and their burgeoning use in vivo as diagnostic probes. For example, gallium and indium radionuclides are used in radiopharmaceuticals. Further, the physical properties of the lanthanides are exploited as luminescent, EPR, and NMR shift probes. They also have widespread application as magnetic resonance imaging contrast agents. Similarities in oxophilicity (e.g. Al(III), Ln(III) and ionic radii (e.g. In(III), Ln(III) do not necessarily result in a complementary chemistry for the respective group 13 and lanthanide ions.
An N403 tripodal tren-based (aminomethylene)phosphinato ligand tris(4-(phenylphosphinato)-3-methyl-3-azabutyl)amine (H3ppma) has been synthesized, and its complexation properties with the group 13 metals Al, Ga, and In have been investigated. The molecular structure of the indium complex [In(H3ppma)2](N03)3 ~ 3H20 (C~H~-InN110zaP6) has been solved by X-ray methods;
the complex crystallizes in the trigonal space group R3c, with a = 18.984(3) A, c =
36.256(5) A, and Z = 6. The structure was solved by Patterson methods and was refined by full-matrix least-squares procedures to R = 0.040 (RW = 0.039) for reflections with I > 3Q(I). The structure of the bis-complex showed the ligand to coordinate in a tridentate manner through the three phosphinate oxygens, resulting in a bicapped octahedral structure of exact S6 symmetry. The solved structure was of the RRRSSS diastereomer, where half of the molecule contained phosphorus atoms of R chirality and the other half contained phosphorus atoms of S chirality.
The highly symmetric 'environment about the metal atoms produces a low electric field gradient at the metal nucleus leading to unusually narrow line widths in the 2'Al, 'lGa, and "SIn NMR spectra. The aluminum complex [Al(H3ppma)2](N03)3 - 2H20 exhibited an extremely rare example of aluminum-phosphorus coupling ion both the 31P and 2'Al NMR spectra, where ZJAIP was shown from both spectra to be 6.7 Hz.
The narrow line widths made the complexes amenable to stability constant studies via a combination of z'Al, 'lGa, and 3'P NMR spectroscopies (25°C). The formation constants for In3+ (log (32 >_ 5.4), Ga3+ (log (32 = 4.24), and Al3+ (log (31 = 0.93, log /32 = 3.45) decrease by an order of magnitude as the group is ascended, consistent with increasing steric interactions of the phenyl groups as the two trisphosphinate ligands are crowded together in order to coordinate the smaller metal ions. Variable temperature Z'Al and 31P NMR spectroscopic studies indicated the RRRSSS diastereomer to be rigid up to 55°C in CD30D.
The results of this work were published in J. Am. Chem. Soc. 1996, 118, 10446-10456, under the title "Highly Symmetric Group 13 Metal-Phosphinato Complexes: Multinuclear NMR (~'Al, 3~p, "Ga) Determination of Stability Constants at Low pH", Mark P. Lowe, Steven J. Rettig, and Chris Orvig. The full disclosure in this article is incorporated in the specification herein by reference.
U. S. Patent No. 4,110,100, Franz et al. , issued August 29, 1978, discloses phosphinylmethyl-imino-acetic acid N-oxide compounds and their use in increasing sucrose content in sugar cane.
FIELD OF THE INVENTION
The invention relates to novel complexes comprising a metal ion and a ligand which incorporates a bipodal backbone. More particularly, the invention pertains to a bipodal ligand bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (HSxuta) which forms novel coordination compounds with a variety of metal ions, particularly, but not exclusively, trivalent metal ions and lanthanide metal ions, which are useful in nuclear medicine.
BACKGROUND OF THE INVENTION
In recent years, vigorous research activity has been conducted to identify and synthesize suitable chelating agents for metal ions and particularly trivalent metal ions such as the group 13 metals and the lanthanides, for use in nuclear medicine. This is because of the deleterious effects of these metals (e.g.
concern over aluminum neurotoxicity) in unprotected form and their burgeoning use in vivo as diagnostic probes. For example, gallium and indium radionuclides are used in radiopharmaceuticals. Further, the physical properties of the lanthanides are exploited as luminescent, EPR, and NMR shift probes. They also have widespread application as magnetic resonance imaging contrast agents. Similarities in oxophilicity (e.g. Al(III), Ln(III) and ionic radii (e.g. In(III), Ln(III) do not necessarily result in a complementary chemistry for the respective group 13 and lanthanide ions.
An N403 tripodal tren-based (aminomethylene)phosphinato ligand tris(4-(phenylphosphinato)-3-methyl-3-azabutyl)amine (H3ppma) has been synthesized, and its complexation properties with the group 13 metals Al, Ga, and In have been investigated. The molecular structure of the indium complex [In(H3ppma)2](N03)3 ~ 3H20 (C~H~-InN110zaP6) has been solved by X-ray methods;
the complex crystallizes in the trigonal space group R3c, with a = 18.984(3) A, c =
36.256(5) A, and Z = 6. The structure was solved by Patterson methods and was refined by full-matrix least-squares procedures to R = 0.040 (RW = 0.039) for reflections with I > 3Q(I). The structure of the bis-complex showed the ligand to coordinate in a tridentate manner through the three phosphinate oxygens, resulting in a bicapped octahedral structure of exact S6 symmetry. The solved structure was of the RRRSSS diastereomer, where half of the molecule contained phosphorus atoms of R chirality and the other half contained phosphorus atoms of S chirality.
The highly symmetric 'environment about the metal atoms produces a low electric field gradient at the metal nucleus leading to unusually narrow line widths in the 2'Al, 'lGa, and "SIn NMR spectra. The aluminum complex [Al(H3ppma)2](N03)3 - 2H20 exhibited an extremely rare example of aluminum-phosphorus coupling ion both the 31P and 2'Al NMR spectra, where ZJAIP was shown from both spectra to be 6.7 Hz.
The narrow line widths made the complexes amenable to stability constant studies via a combination of z'Al, 'lGa, and 3'P NMR spectroscopies (25°C). The formation constants for In3+ (log (32 >_ 5.4), Ga3+ (log (32 = 4.24), and Al3+ (log (31 = 0.93, log /32 = 3.45) decrease by an order of magnitude as the group is ascended, consistent with increasing steric interactions of the phenyl groups as the two trisphosphinate ligands are crowded together in order to coordinate the smaller metal ions. Variable temperature Z'Al and 31P NMR spectroscopic studies indicated the RRRSSS diastereomer to be rigid up to 55°C in CD30D.
The results of this work were published in J. Am. Chem. Soc. 1996, 118, 10446-10456, under the title "Highly Symmetric Group 13 Metal-Phosphinato Complexes: Multinuclear NMR (~'Al, 3~p, "Ga) Determination of Stability Constants at Low pH", Mark P. Lowe, Steven J. Rettig, and Chris Orvig. The full disclosure in this article is incorporated in the specification herein by reference.
U. S. Patent No. 4,110,100, Franz et al. , issued August 29, 1978, discloses phosphinylmethyl-imino-acetic acid N-oxide compounds and their use in increasing sucrose content in sugar cane.
An article entitled "Organische Phosphor-Verbindungen 72, Herstelling and Eigenschaften von Bis (N-hydroxycarbonyl-methylaminomethyl) phosphinsaure (HOZCCHZNHCH2)zP(O)OH, and Derivaten", Maier et al., Phosphorus aYtd Su~r, 1980, vol. 8, pp. 67-72, discloses the production of (HOZCCHZN(R)OH2)2P(O)OH
from iminodiacetic acid and benzlgycine with formaldehyde and hypophosphorous acid.
An article in Synthetic Communications 27(17), pp. 2899-2903, (1997) entitled "Synthesis of Bis (Aminomethyl) Phosphinic Acids Via a Mannich Reaction", Varga, discloses the production of N, N, N', N'-Tetrasubstituted bis (aminomethyl) phosphinic acid from iminoacids, paraformaldehyde and aqueous phosphinic acid.
SUMMARY OF THE INVENTION
The invention relates to novel complexes of a metal ion and a ligand which has a bipodal backbone. In a particular embodiment, the novel complexes comprise bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta) ((HOZCCHZ)zNCH2)zPOaH
with technetium (Tc) and rhenium (Re) and any one of the group 13 metals, Al, Ga and In, and any one of the rare earth metals, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
Bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid has the following graphic formula:
O
~~~~N~IP~N O
~O_ ~O xutas-O O
from iminodiacetic acid and benzlgycine with formaldehyde and hypophosphorous acid.
An article in Synthetic Communications 27(17), pp. 2899-2903, (1997) entitled "Synthesis of Bis (Aminomethyl) Phosphinic Acids Via a Mannich Reaction", Varga, discloses the production of N, N, N', N'-Tetrasubstituted bis (aminomethyl) phosphinic acid from iminoacids, paraformaldehyde and aqueous phosphinic acid.
SUMMARY OF THE INVENTION
The invention relates to novel complexes of a metal ion and a ligand which has a bipodal backbone. In a particular embodiment, the novel complexes comprise bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta) ((HOZCCHZ)zNCH2)zPOaH
with technetium (Tc) and rhenium (Re) and any one of the group 13 metals, Al, Ga and In, and any one of the rare earth metals, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
Bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid has the following graphic formula:
O
~~~~N~IP~N O
~O_ ~O xutas-O O
The invention is also directed to a process of chelating a trivalent metal ion such as Technetium (Tc) or Rhenium (Re) or a trivalent metal ion of the group 13 metals and the rare earths which comprises complexing Tc or Re or any one of the group 13 metals, Al, Ga and In, and any one of the rare earths or lanthanides, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, with bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta).
In the process of the invention, Tc or Re or any one of the group 13 metals, Al, Ga and In or any one of the rare earth metals, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, can be complexed with the HSxuta ligand. The invention also includes the chelation of Beta emitting radioactive isotopes as therapeutic agents, including but not limited to the isotopes Sm 153, Ho 166, Y 90, Pm 149, Pr 145, Dy 166, Ln 177 and Yb, and for imaging applications including but not limited to In 111.
The invention also pertains to the use of novel complexes of Hsxuta and Tc, Re, or any one of the group 13 metals, Al, Ga and In, and any one of the rare earth metals or lanthanides, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, in diagnostic and therapeutic nuclear medicine.
BRIEF DESCRIPTION OF DRAWINGS
In drawings which illustrate specific embodiments of the invention, but which should not be construed as restricting the spirit or scope of the invention in any way:
Figure 1 illustrates the graphical formulae for H3ppma, H6trns, H6tams and H6taps.
. Figure 2 illustrates a graphical scheme for complexing bicapped, monocapped, and encapsulated configurations.
In the process of the invention, Tc or Re or any one of the group 13 metals, Al, Ga and In or any one of the rare earth metals, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, can be complexed with the HSxuta ligand. The invention also includes the chelation of Beta emitting radioactive isotopes as therapeutic agents, including but not limited to the isotopes Sm 153, Ho 166, Y 90, Pm 149, Pr 145, Dy 166, Ln 177 and Yb, and for imaging applications including but not limited to In 111.
The invention also pertains to the use of novel complexes of Hsxuta and Tc, Re, or any one of the group 13 metals, Al, Ga and In, and any one of the rare earth metals or lanthanides, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, in diagnostic and therapeutic nuclear medicine.
BRIEF DESCRIPTION OF DRAWINGS
In drawings which illustrate specific embodiments of the invention, but which should not be construed as restricting the spirit or scope of the invention in any way:
Figure 1 illustrates the graphical formulae for H3ppma, H6trns, H6tams and H6taps.
. Figure 2 illustrates a graphical scheme for complexing bicapped, monocapped, and encapsulated configurations.
DETAILED DESCRIPTION OF THE INVENTION
The inventors herein have previously conducted considerable investigation into the use of amine phosphinate tripodal ligands such as H3ppma, H3hpma and H3pma in the chelation of metal ions and particularly a trivalent metal ion of the group 13 metals, Al, Ga and In, and Tc or Re, and any one of the rare earths, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
The inventors have now discovered that a bipodal ligand, bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta); can be used to chelateany one of the foregoing trivalent metals. It should be helpful for background purposes and a full understanding of the invention relating to bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta) as a chelating agent, to review the characteristics and behaviour of H3ppma, H3hpma and H3pma in chelation of the foregoing trivalent metals.
General Synthetic Procedure for Preparing H3ppma, H3hpma and H3pma. The appropriate tripodal amine (derivatives of tren and tame specifically) are reacted with a suitable phosphinic acid and formaldehyde under Moedritzer-Irani synthesis (Moedritzer, K., Irani, R.R., J. Org. Chem. 1966, 31, 1603) conditions as shown below for H3pma and H3ppma. The P-H derivatives such as H3pma can then be used to make further derivatives as is shown below for H3hpma.
~N~ iCH3 H3C- NH* NH* NH*
H3C~ ~ 1 R-_ C6~I5 H3Ppma P G ~, R R-__ C~I~OH H3hpma H- p~~~R 0 R. H H3pma Examples Tris(4-phosphinato-3-methyl-3-azabutyl)amine (H3pma). A stirred solution of tris(3-methyl-3-azabutyl)amine (0.50 g, 2.66 mmol) and 50% H3P02 (1.40 g, 10.61 mmol) in H20 (7 mL) was heated to 40°C. This amine was synthesized by the reaction of tren with ethylchloroformate followed by the reduction of the resulting carbamate with lithium aluminum hydride to give the tri-N-methylated amine:
Schmidt, H. , Lensink, C. , Xi, S.K. , Verkade, J. G. Z. Anorg. Allg. Chem.
1989, 578, 75. Paraformaldehyde (0.32 g, 10.67 mmol) was slowly added over 1 hr. The reaction was heated for a further 4 hours and then the solvent removed to yield a colorless oil. The oil was taken up in Hz0 (10 mL), loaded onto an anion exchange column (Amberlite IRA 412) and eluted with water to remove any unreacted H3P02 or biproduct (HOCHzPH(O)OH). On removal of the solvent, a colorless oil was obtained of H3pma.2HC1.4H20. Yield = 1.21 g (78 % ). 'H NMR (200 MHz, D20) pD = 6.83: 8 2.96 (t, 6H, ethylenic CHZ 3JHH = 6.6 Hz), 3.30 (t, 6H, ethylenic CH2, 3JHH = 6.6 Hz), 2.85 (s, 9H, methyl NCH3), 3.14 (d, 6H, methylenic NCH2P, 2JPH
= 10.5 Hz), 7.17 (d, 3H, phosphinic PH, 3JPH = 540.4 Hz). 3'P{H} (80 MHz, D20) pD = 6.83: 8 12.45.
Tris(4-phenylphosphinato-3-methyl-3-azabutyl)amine trihydrochloride monohydrate (H3ppma ~ 3HC1 ~ H20). Phenylphosphinic acid (2.13 g, 14.99 mmol) and tris(3-azabutyl)amine (0.91 g, 4.83 mmol) were dissolved in distilled water (20 mL). After slow addition of 37% HCl (20 mL), the temperature of the stirred solution was raised to reflux (~ 110°C) and 37% w/w aqueous formaldehyde (2.44 g, 30.09 mmol) was added dropwise over a period of 30 min.
The reaction was refluxed for a further 5 hours, after which time the HCl -water solvent mixture was concentrated under vacuum almost to dryness. The resulting syrup was taken up in ethanol (100 mL), and acetone (900 mL) was added to give a cloudy solution which was cooled, then filtered. A white highly hygroscopic powder was obtained; this was taken up in water and the solvent removed once more.
Drying under vacuum for 12 hours gave a glassy, slightly hygroscopic solid to yield 2.40 g _7_ (64 % ); Anal. Calcd (found) for C3oIi45N4O6P3 ~ 3HC1 ~ H20: C, 46.31 (46.58);
H, 6.48 (6.48): N, 7.20 (7.31). Potentiometric studies were consistent with this molecular weight. Mass spectrum (+LSIMS):m/z = 651 ([L+1]+,[C3oH46N4O6P3]+)~ IR (cm 1, KBr disk): 3410, 2460 (b s, N-H, o-H), 1645 (w, N-H), 1438 (s, P-Ph), 1206, 1131, 957 (P-o), 740, 685, 599 (P-e, p_p~. UV (",~, nm (,M-lclri 1)): pH = 1.5, 258 (1375), 264 (1833), 271 (1512).
Tris (4-hydroxymethylenephosphinato-3-methyl-3-azabutyl) amine (H3hpma). A stirred solution of H3pma.2HC1.4Hz0 (0.22 g, 0.28 mmol) in 6M HCl (20 mL) was heated to reflux. Aqueous 37 % formaldehyde (0.25 g. 3.08 mmol) was slowly added over 1 hour. The reaction was heated at reflux overnight and then the solvent removed under vacuum to yield a colorless oil. The oil was taken up in (10 mL), loaded onto an anion exchange column (Amberlite IRA 412) and eluted with water. On removal of the solvent, a colorless oil was obtained of H3hpma.4HC1.7H20. 0.387 g was obtained, but there was a lot of HCl and HZO
still present. Potentiometry indicated that 0.387 g contained 0.48 mmol of ligand, therefore Mw = 792.12. Mw without HCl or water is 512.42, which leaves an extra 283.41. Potentiometry gives the excess acid as about 4 HCl which means about 7 waters. An alternative method is to do the H3pma reactions as before and then carry on with more paraformaldehyde at 100°C in same solution, i.e. avoid the HCl treatment. After passing through anion exchange, there is .3HC1 (from column) and one water c.f. H3ppma, H3pma. 1H NMR (200 MHz, D20) pD = 7.03: 8 3.00 (t, 6H, ethylenic CHZ), 3.41 (t, 6H, ethylenic CHZ), 2.94 (s, 9H, methyl NCH3), 3.30 (d, 6H, methylenic NCHZP, ZJPH = 8.54 Hz), 3.68 (d, 6H, hydroxymethylene HOCH2P, ZJPH = 6.35 Hz). 31P{H} (80 MHz, D20) pD = 7.03: 8 27.35.
The following pertains specifically to bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid.
Bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta ~ HCl ~ 0.5H20) . Iminodiacetic acid (2.66 g, 20 mmol) and 50 %
aqueous _ g _ soluton of phosphinic acid (1.32 g, 10 mmol) were dissolved in refluxing 6M
(4 g). To the hot mixture, aqueous formaldehyde (37% w/w solution, 3.2 g) was added dropwise, and the resulting solution was refluxed for 16 hr. Upon cooling, a white precipitate formed and was filtered out, washed with cold methanol and dried under vacuum (50 % ). Anaal. Calcd (found) for CloH1,N201oP ~ HCl ~ O.SH20: C, 29.91); H, 4.77 (4.96); N, 6.97 (6.73). Hsxuta ~ HCl 1H NMR (200MHz, D20): 3.6 ppm (d, 4H, NCHZP, ZJ~H=lOHz); 4.2 ppm (s, 8H, CCHZN). 31P{H} (80 MHz, D20): 17.8 ppm.
Synthesis of bis-{[bis-(carboJrymethyl)-amino]-methyl}-phosphinic acid (HSxuta) . The synthesis of bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta) has been reported in Maier, L. and Smith, J.J., Phosphorus and Sulfur, 1980, vol. 8, 67, the subject matter of which is incorporated herein by reference.
Reaction conditions were slightly modified for this application.
The chelation of metal ions and trivalent metal ions such as Tc and Re and the group 13 metals and the lanthanides with a variety of mixed nitrogen/oxygen donors in amine phosphinate tripodal ligands have previously been investigated by the inventors herein. However, until the water soluble sulphonated analogs were synthesized, little was known of the solution behavior. The coordination mode of the ligand can be metal dependent. For instance, in aqueous solution Hbtrns (see Figure 1) forms bicapped bis(ligand) lanthanide complexes in which bonding is solely through the phenolic oxygens, whereas the Ga(III) and In(III) form 1:1 encapsulated complexes in which bonding occurs with both oxygen and nitrogen donors, while Al(III) does not form a stable complex with Hbtrns in aqueous solution. The capped and bicapped lanthanide complexes of H6trns have 16 membered chelate rings, much larger than the 5 and 6 membered rings in the encapsulated complexes. It has been suggested that there is an effect which predisposes the ligand to a binding posture, for example the inter and intrastrand hydrogen bonding between protonated nitrogens and phenolic oxygens. The hydrogen bonding, coupled with the large chelate ring size, can result in a ligand which suffers little or no strain energy in accommodating different sized lanthanide ions, and thus the changes in stability noted (an unprece-dented 5 orders of magnitude increase in stability from Nd - Yb) correlated with the increasing effective nuclear charge.
In an effort to gain some further insight into the aqueous chemistry of Hbtrns with the lanthanides, the aqueous lanthanide coordination chemistry of two other smaller tripodal aminephenol ligands, H6tams and Hbtaps (see Figure 1), were investigated. If these ligands coordinate in a similar manner as H3trns'-(bicapped), 14 and 13-membered chelate rings would be formed upon lanthanide coordination.
The effect of the large chelate ring size on metal ion stability and selectivity was of interest. There has been no structural chemistry reported for either the Ln -tams or Ln - taps systems. However, as was seen with the group 13 metals, variations in the number of potential donor atoms, the number of chelate rings formed upon coordination, and the size of the chelate rings formed (5- or 6-membered rings) can have a profound effect upon metal ion selectivity and coordination geometry (see Figure 2). Instead, this change in backbone resulted in a dramatic change in binding modality in that Hbtams and Hbtaps react with Ln(III) ions in the presence of base to form encapsulated complexes wherein all 6 donor atoms of the ligand (i. e.
N3O, coordination) coordinate to the lanthanide ion. This change in coordination mode relative to Hbtrns (capped, bicapped) also produces a lower selectivity for heavy lanthanide chelation.
Changing the phenolic oxygen donor atoms of Hbtrns to phosphinic acids, H,ppma (see Figure 1), resulted in bicapped binding for the group 13 metals (see Figure 2). The first stepwise equilibrium constant K, (formation of the monocapped species) is less than that of the second Kz (formation of the bicapped species). This behavior was also noted in the lanthanide H3trns~- system. It was found that the difference between K, and KZ increased as the metal ion size increased.
In light of this size effect, this phenomenon was explored further by using larger metal ions, i.e. the lanthanides. The results of the reactions of Ln(III) with H3ppma demonstrate, once more, that bicapped species are formed. The anomalous equilib-rium constant behavior was also observed and is discussed in relation to the similar trend observed for Hbtrns, whereby the anomaly can be described in terms of hydrophobic effects.
Examples of Metal Complexes Comprising Amine Phosphinate Tripodal Ligands Materials. Sodium deuteroxide (NaOD, 40%), deuterium chloride (DCI, 12M) and the lanthanide atomic absorption standards were obtained from Aldrich. Hydrated lanthanide nitrates and chlorides were obtained from Alfa.
Deuterium oxide (D20) and methanol-d, (CD,OD) and DMSO-d6 were purchased from Cambridge Isotope Laboratories. All were used without further purification.
Tris(4-phenylphosphinato-3-methyl-3-azabutyl)amine trihydrochloride monohydrate (H3ppma~3HC1~Hz0),8 1,1,1-tris(((2-hydroxy-5-sulfobenzyl)amino)methyl)ethane dihemihydrate (H6tams~2.5H20)6 and 1,2,3-tris((2-hydroxy-5-sulfobenzyl)amino)propane dihemihydrate (H6taps~2.5Hz0)6 were prepared as described in published papers.
Instruments. 'H NMR spectra (200 and 300 MHz) were referenced to DSS or TMS and recorded on Bruker AC-200E and Varian XL 300 spectrometers.
"C NMR (75.5 MHz, referenced to DSS or TMS), "P NMR (121.0 MHz, referenced to external 85 % H,PO,), natural abundance "O NMR (40.7 MHz, referenced to H20), and "9La NMR (42.4 MHz, referenced to 0.1 M La(C104) in 1 M HC10,) spectra were recorded on the latter instrument. Mass spectra were obtained on a Kratos Concept II H32Q (Cs+, LSIMS) instrument with thioglycerol or 3-nitrobenzyl alcohol as the matrix. Infrared spectra were obtained as KBr disks in the range 4000 -cm-' on a Galaxy Series 5000 FTIR spectrometer. Analyses for C, H, and N were performed.
Synthesis of Lanthanide-H,ppma Complexes. The preparation of the lutetium complex (as the trihydrate) is representative for the lanthanides Er -Lu and the preparation of the terbium complex (as the pentahydrate) is representative for the lanthanides Sm - Ho, Yb, Lu (in the case of Sm, Eu and Ho the metal chloride was used). All the complexes prepared and their elemental analyses, mass spectral, infrared and NMR data are listed in Tables 1 - 4.
[Lu(H,ppma)~] [NO,],.3H20. The pH of an aqueous solution (4 mL) of H,ppma.3HCl.HzO (0.200 g, 0.257 mmol) and Lu(N03),.6Hz0 (0.060 g, 0.128 mmol) was raised to 2.0 using 3M NaOH. Colorless prisms deposited after 2 hours;
these prisms were filtered and dried under vacuum to yield 0.145 g (66.0 % ) . Yield for Yb 78.4%, Tm 50.2%, Er 53.0%.
[Tb(H,ppma)~][NO,],.5Hz0. An aqueous solution (0.7 mL) of H,ppma.3HC1.H20 (0.100 g, 0.128 mmol) was added to Tb(NO,),.5H20 (0.057 g, 0.128 mmol) in 0.7 mL of H20. Colorless hexagonal crystals deposited after 24 hours; these were filtered and dried under vacuum to yield 0.064 g (57.6 % ).
Yields for Lu 70. 5 % , Yb 73 .4 % , Ho 43 .2 % , Dy 50.1 % , Gd 63 .1 % , Eu 40. 3 %
, Sm 47.9 % .
NMR Measurements. The variable pH 'H NMR spectra of the H6tams and Hbtaps complexes were run in DZO with the pD values being measured by a Fisher Accumet 950 pH meter employing an Accumet Ag/AgCI combination microelectrode. The pD values were converted to pH by adding 0.40 to the observed reading. The "O NMR experiments with Dy(III) were recorded at 21°C, with a spectral window of 1000 Hz, a 90° pulse width of 18 ms, and an acquisition time of 0.256 s; this gave 512 data points. Two thousand transients were collected per spectrum. The "O linewidths for Hz0 were about 60 Hz. Concentrations employed ranged from 1 to 40 mM. The dysprosium induced shifts (DIS) were obtained from the observed shift by making a correction for the bulk magnetic susceptibility of the solution. Stock solutions were prepared from metal nitrates in DZO (H20) and the metal-ligand solutions were prepared by pipetting required amounts of stock solution and adjusting the pH with acid or base. In the equilibrium measurements, the ionic strength was controlled by addition of NaCI.
For the Ln - H,ppma (Ln = Yb, Lu) equilibrium constant studies using 3'P{H} NMR, conditions as described in a previous publication were used. Metal ion stock solutions (50 mM) were prepared from the hydrates of Lu(NO,), and Yb(N03)3.
All solutions contained a fixed amount of M'+ (25 mM) with the ligand concentration varied (R = [L]T/[M]T) as 0.25 < R < 4. Solutions were made up to a volume of 0.8 mL and the pH was adjusted to 1.5. The solutions were allowed to equilibrate for 48 hours prior to the spectra being collected. The respective peak integrals enabled a quantitative measurement (long delay times of 1.6 s were employed) of free ligand ([L]). The knowledge of [L] allowed n, the ratio of bound ligand to total metal to be calculated (n = ([L]T [L])/[M]T). A plot of n vs. [L] resulted in a curve from which the variables ~3, and X32 could be calculated using computer curve fitting software.
Potentiometric Equilibrium Measurements. The measurements were made at 25.0 t 0.1°, m = 0.16 M NaCI. The pKas of the ligands were checked whenever a different synthetic batch of ligand was used, and fresh ligand solutions were always employed (For Hbtaps: pKal = 1.7, pKa2 = 6.54, pKa3 = 7.78, pKa4 = 8.73, pKaS = 9.77, pKa6 = 11.24 and for Hbtams: pKal = 2.92, pKa2 = 6.56, pKa3 = 7.95, pKa4 = 8.91, pKaS = 9.81, pKa6 = 11.19).6 The lanthanide solutions were prepared by dilution of the appropriate atomic absorption standards.
Since the lanthanides do not hydrolyze below pH 6, the excess acid in the solutions could be obtained by titrating with standard NaOH and analyzing for the strong acid by the method of Gran.
The ratio of ligand to metal used was 1:2 < L:M < 4:1. Concentrations were in the range 0.5 - 2.5 mM. A minimum of five titrations were performed for each metal. The metal - Hbtaps and metal - Hbtams solutions were titrated to just beyond six equivalents NaOH /H~ ~,btams), because of slow hydrolysis beyond this point. Although complexation was rapid (1-3 min per point to give a stable pH
reading), care was taken to ensure that no trace hydrolysis or precipitation was occurring by monitoring up to 30 minutes for pH drift. The protonation constants for the lanthanide-ligand stability constants were determined by using the program BEST.1 Hbtams and Hbtaps, both reacted with Ln(III) to coordinate as hexadentate ligands, liberating six equivalents of acid per ligand. Typically 100 data points were collected with about 80-90 % of the points being in the buffer region of metal-ligand complexation and the remaining points in the strong acid region being used as a check of excess acid concentration.
X=ray Crystallographic Analyses of [C~H~LuN80,~ (NO,); 3HZO. Selected crystallographic data appear in Table 5. The final unit-cell parameters were obtained by least-squares on the setting angles for 25 reflections with 2 = 55.7-68.7 ° . The intensities of three standard reflections, measured every 200 reflections throughout the data collection, decayed linearly by 2.7 % . The data were processed and corrected for Lorentz and polarization effects, decay, and absorption (empirical, based on azimuthal scans).
The structure of [C~Ii~I,uNgO,z](NO,),~3Hz0 was solved by the Patterson method. The structure analysis was initiated in the centrosymmetric space group R c on the basis of the E statistics, this choice being confirmed by subsequent calcula-tions. The nitrate anions and water molecules were modeled as ( 1:1 ) disordered about a point of S6 symmetry. Because of thermal motion and near overlap of disordered components, the nitrate groups deviate from ideal geometry. Refinement of the structure in the noncentrosymmetric space group R3c failed to resolve the disorder.
All non-hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were fixed in calculated positions (N-H = 0.91 fir, C-H = 0.98 A, BH =
1.2 B~"~ ,~",). A correction for secondary extinction (Zacharaisen type) was applied, the final value of the extinction coefficient being 1.73(3) x 10-'. Neutral atom scattering factors for all atoms and anomalous dispersion corrections for the non-hydrogen atoms were taken from the International Tables for X Ray Crystallography.
Selected bond lengths and bond angles appear in Table 6. Complete tables of crystallographic data, final atomic coordinates and equivalent isotropic thermal parameters, anisotropic thermal parameters, bond lengths, bond angles, torsion angles, intermolecular contacts, and least-squares planes are included as Supporting Information.
Examples of Metal Complexes Comprising Bipodal Li~ands Synthesis of Lanthanide-xuta complexes. Three lanthanide complexes (La, Ho and Sm) were made and partially characterized. A general procedure for making the complexes is as follows: metal chloride (0.2 mmol) and Hsxuta ~ HCl (0.2 mmol) was dissolved in 7 mL water and the pH of the solution was raised to 6 -with 1 M KOH. Methanol was added until a precipitate formed, and this precipitate was collected and dried under vacuum to yield about 0.16 mmol (80 % ) of KZ[Ln(xuta)].
Preliminary studies of bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta) with the lanthanides indicates that complex formation takes place at 1:1 metal to ligand ratio over a wide range of pH values. The lanthanide complexes are deliquescent.
The ligand ((HOZCCH2)zNCH2)2POZH (HSxuta) complexes metal ions at three sites and at intermediate pH levels, which increases the stability of the resulting complex.
As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this 2invention without departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims.
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Choppin, G.R., Eds.; Elsevier: Amsterdam, 1989.
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The inventors herein have previously conducted considerable investigation into the use of amine phosphinate tripodal ligands such as H3ppma, H3hpma and H3pma in the chelation of metal ions and particularly a trivalent metal ion of the group 13 metals, Al, Ga and In, and Tc or Re, and any one of the rare earths, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
The inventors have now discovered that a bipodal ligand, bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta); can be used to chelateany one of the foregoing trivalent metals. It should be helpful for background purposes and a full understanding of the invention relating to bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta) as a chelating agent, to review the characteristics and behaviour of H3ppma, H3hpma and H3pma in chelation of the foregoing trivalent metals.
General Synthetic Procedure for Preparing H3ppma, H3hpma and H3pma. The appropriate tripodal amine (derivatives of tren and tame specifically) are reacted with a suitable phosphinic acid and formaldehyde under Moedritzer-Irani synthesis (Moedritzer, K., Irani, R.R., J. Org. Chem. 1966, 31, 1603) conditions as shown below for H3pma and H3ppma. The P-H derivatives such as H3pma can then be used to make further derivatives as is shown below for H3hpma.
~N~ iCH3 H3C- NH* NH* NH*
H3C~ ~ 1 R-_ C6~I5 H3Ppma P G ~, R R-__ C~I~OH H3hpma H- p~~~R 0 R. H H3pma Examples Tris(4-phosphinato-3-methyl-3-azabutyl)amine (H3pma). A stirred solution of tris(3-methyl-3-azabutyl)amine (0.50 g, 2.66 mmol) and 50% H3P02 (1.40 g, 10.61 mmol) in H20 (7 mL) was heated to 40°C. This amine was synthesized by the reaction of tren with ethylchloroformate followed by the reduction of the resulting carbamate with lithium aluminum hydride to give the tri-N-methylated amine:
Schmidt, H. , Lensink, C. , Xi, S.K. , Verkade, J. G. Z. Anorg. Allg. Chem.
1989, 578, 75. Paraformaldehyde (0.32 g, 10.67 mmol) was slowly added over 1 hr. The reaction was heated for a further 4 hours and then the solvent removed to yield a colorless oil. The oil was taken up in Hz0 (10 mL), loaded onto an anion exchange column (Amberlite IRA 412) and eluted with water to remove any unreacted H3P02 or biproduct (HOCHzPH(O)OH). On removal of the solvent, a colorless oil was obtained of H3pma.2HC1.4H20. Yield = 1.21 g (78 % ). 'H NMR (200 MHz, D20) pD = 6.83: 8 2.96 (t, 6H, ethylenic CHZ 3JHH = 6.6 Hz), 3.30 (t, 6H, ethylenic CH2, 3JHH = 6.6 Hz), 2.85 (s, 9H, methyl NCH3), 3.14 (d, 6H, methylenic NCH2P, 2JPH
= 10.5 Hz), 7.17 (d, 3H, phosphinic PH, 3JPH = 540.4 Hz). 3'P{H} (80 MHz, D20) pD = 6.83: 8 12.45.
Tris(4-phenylphosphinato-3-methyl-3-azabutyl)amine trihydrochloride monohydrate (H3ppma ~ 3HC1 ~ H20). Phenylphosphinic acid (2.13 g, 14.99 mmol) and tris(3-azabutyl)amine (0.91 g, 4.83 mmol) were dissolved in distilled water (20 mL). After slow addition of 37% HCl (20 mL), the temperature of the stirred solution was raised to reflux (~ 110°C) and 37% w/w aqueous formaldehyde (2.44 g, 30.09 mmol) was added dropwise over a period of 30 min.
The reaction was refluxed for a further 5 hours, after which time the HCl -water solvent mixture was concentrated under vacuum almost to dryness. The resulting syrup was taken up in ethanol (100 mL), and acetone (900 mL) was added to give a cloudy solution which was cooled, then filtered. A white highly hygroscopic powder was obtained; this was taken up in water and the solvent removed once more.
Drying under vacuum for 12 hours gave a glassy, slightly hygroscopic solid to yield 2.40 g _7_ (64 % ); Anal. Calcd (found) for C3oIi45N4O6P3 ~ 3HC1 ~ H20: C, 46.31 (46.58);
H, 6.48 (6.48): N, 7.20 (7.31). Potentiometric studies were consistent with this molecular weight. Mass spectrum (+LSIMS):m/z = 651 ([L+1]+,[C3oH46N4O6P3]+)~ IR (cm 1, KBr disk): 3410, 2460 (b s, N-H, o-H), 1645 (w, N-H), 1438 (s, P-Ph), 1206, 1131, 957 (P-o), 740, 685, 599 (P-e, p_p~. UV (",~, nm (,M-lclri 1)): pH = 1.5, 258 (1375), 264 (1833), 271 (1512).
Tris (4-hydroxymethylenephosphinato-3-methyl-3-azabutyl) amine (H3hpma). A stirred solution of H3pma.2HC1.4Hz0 (0.22 g, 0.28 mmol) in 6M HCl (20 mL) was heated to reflux. Aqueous 37 % formaldehyde (0.25 g. 3.08 mmol) was slowly added over 1 hour. The reaction was heated at reflux overnight and then the solvent removed under vacuum to yield a colorless oil. The oil was taken up in (10 mL), loaded onto an anion exchange column (Amberlite IRA 412) and eluted with water. On removal of the solvent, a colorless oil was obtained of H3hpma.4HC1.7H20. 0.387 g was obtained, but there was a lot of HCl and HZO
still present. Potentiometry indicated that 0.387 g contained 0.48 mmol of ligand, therefore Mw = 792.12. Mw without HCl or water is 512.42, which leaves an extra 283.41. Potentiometry gives the excess acid as about 4 HCl which means about 7 waters. An alternative method is to do the H3pma reactions as before and then carry on with more paraformaldehyde at 100°C in same solution, i.e. avoid the HCl treatment. After passing through anion exchange, there is .3HC1 (from column) and one water c.f. H3ppma, H3pma. 1H NMR (200 MHz, D20) pD = 7.03: 8 3.00 (t, 6H, ethylenic CHZ), 3.41 (t, 6H, ethylenic CHZ), 2.94 (s, 9H, methyl NCH3), 3.30 (d, 6H, methylenic NCHZP, ZJPH = 8.54 Hz), 3.68 (d, 6H, hydroxymethylene HOCH2P, ZJPH = 6.35 Hz). 31P{H} (80 MHz, D20) pD = 7.03: 8 27.35.
The following pertains specifically to bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid.
Bis-{[bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta ~ HCl ~ 0.5H20) . Iminodiacetic acid (2.66 g, 20 mmol) and 50 %
aqueous _ g _ soluton of phosphinic acid (1.32 g, 10 mmol) were dissolved in refluxing 6M
(4 g). To the hot mixture, aqueous formaldehyde (37% w/w solution, 3.2 g) was added dropwise, and the resulting solution was refluxed for 16 hr. Upon cooling, a white precipitate formed and was filtered out, washed with cold methanol and dried under vacuum (50 % ). Anaal. Calcd (found) for CloH1,N201oP ~ HCl ~ O.SH20: C, 29.91); H, 4.77 (4.96); N, 6.97 (6.73). Hsxuta ~ HCl 1H NMR (200MHz, D20): 3.6 ppm (d, 4H, NCHZP, ZJ~H=lOHz); 4.2 ppm (s, 8H, CCHZN). 31P{H} (80 MHz, D20): 17.8 ppm.
Synthesis of bis-{[bis-(carboJrymethyl)-amino]-methyl}-phosphinic acid (HSxuta) . The synthesis of bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta) has been reported in Maier, L. and Smith, J.J., Phosphorus and Sulfur, 1980, vol. 8, 67, the subject matter of which is incorporated herein by reference.
Reaction conditions were slightly modified for this application.
The chelation of metal ions and trivalent metal ions such as Tc and Re and the group 13 metals and the lanthanides with a variety of mixed nitrogen/oxygen donors in amine phosphinate tripodal ligands have previously been investigated by the inventors herein. However, until the water soluble sulphonated analogs were synthesized, little was known of the solution behavior. The coordination mode of the ligand can be metal dependent. For instance, in aqueous solution Hbtrns (see Figure 1) forms bicapped bis(ligand) lanthanide complexes in which bonding is solely through the phenolic oxygens, whereas the Ga(III) and In(III) form 1:1 encapsulated complexes in which bonding occurs with both oxygen and nitrogen donors, while Al(III) does not form a stable complex with Hbtrns in aqueous solution. The capped and bicapped lanthanide complexes of H6trns have 16 membered chelate rings, much larger than the 5 and 6 membered rings in the encapsulated complexes. It has been suggested that there is an effect which predisposes the ligand to a binding posture, for example the inter and intrastrand hydrogen bonding between protonated nitrogens and phenolic oxygens. The hydrogen bonding, coupled with the large chelate ring size, can result in a ligand which suffers little or no strain energy in accommodating different sized lanthanide ions, and thus the changes in stability noted (an unprece-dented 5 orders of magnitude increase in stability from Nd - Yb) correlated with the increasing effective nuclear charge.
In an effort to gain some further insight into the aqueous chemistry of Hbtrns with the lanthanides, the aqueous lanthanide coordination chemistry of two other smaller tripodal aminephenol ligands, H6tams and Hbtaps (see Figure 1), were investigated. If these ligands coordinate in a similar manner as H3trns'-(bicapped), 14 and 13-membered chelate rings would be formed upon lanthanide coordination.
The effect of the large chelate ring size on metal ion stability and selectivity was of interest. There has been no structural chemistry reported for either the Ln -tams or Ln - taps systems. However, as was seen with the group 13 metals, variations in the number of potential donor atoms, the number of chelate rings formed upon coordination, and the size of the chelate rings formed (5- or 6-membered rings) can have a profound effect upon metal ion selectivity and coordination geometry (see Figure 2). Instead, this change in backbone resulted in a dramatic change in binding modality in that Hbtams and Hbtaps react with Ln(III) ions in the presence of base to form encapsulated complexes wherein all 6 donor atoms of the ligand (i. e.
N3O, coordination) coordinate to the lanthanide ion. This change in coordination mode relative to Hbtrns (capped, bicapped) also produces a lower selectivity for heavy lanthanide chelation.
Changing the phenolic oxygen donor atoms of Hbtrns to phosphinic acids, H,ppma (see Figure 1), resulted in bicapped binding for the group 13 metals (see Figure 2). The first stepwise equilibrium constant K, (formation of the monocapped species) is less than that of the second Kz (formation of the bicapped species). This behavior was also noted in the lanthanide H3trns~- system. It was found that the difference between K, and KZ increased as the metal ion size increased.
In light of this size effect, this phenomenon was explored further by using larger metal ions, i.e. the lanthanides. The results of the reactions of Ln(III) with H3ppma demonstrate, once more, that bicapped species are formed. The anomalous equilib-rium constant behavior was also observed and is discussed in relation to the similar trend observed for Hbtrns, whereby the anomaly can be described in terms of hydrophobic effects.
Examples of Metal Complexes Comprising Amine Phosphinate Tripodal Ligands Materials. Sodium deuteroxide (NaOD, 40%), deuterium chloride (DCI, 12M) and the lanthanide atomic absorption standards were obtained from Aldrich. Hydrated lanthanide nitrates and chlorides were obtained from Alfa.
Deuterium oxide (D20) and methanol-d, (CD,OD) and DMSO-d6 were purchased from Cambridge Isotope Laboratories. All were used without further purification.
Tris(4-phenylphosphinato-3-methyl-3-azabutyl)amine trihydrochloride monohydrate (H3ppma~3HC1~Hz0),8 1,1,1-tris(((2-hydroxy-5-sulfobenzyl)amino)methyl)ethane dihemihydrate (H6tams~2.5H20)6 and 1,2,3-tris((2-hydroxy-5-sulfobenzyl)amino)propane dihemihydrate (H6taps~2.5Hz0)6 were prepared as described in published papers.
Instruments. 'H NMR spectra (200 and 300 MHz) were referenced to DSS or TMS and recorded on Bruker AC-200E and Varian XL 300 spectrometers.
"C NMR (75.5 MHz, referenced to DSS or TMS), "P NMR (121.0 MHz, referenced to external 85 % H,PO,), natural abundance "O NMR (40.7 MHz, referenced to H20), and "9La NMR (42.4 MHz, referenced to 0.1 M La(C104) in 1 M HC10,) spectra were recorded on the latter instrument. Mass spectra were obtained on a Kratos Concept II H32Q (Cs+, LSIMS) instrument with thioglycerol or 3-nitrobenzyl alcohol as the matrix. Infrared spectra were obtained as KBr disks in the range 4000 -cm-' on a Galaxy Series 5000 FTIR spectrometer. Analyses for C, H, and N were performed.
Synthesis of Lanthanide-H,ppma Complexes. The preparation of the lutetium complex (as the trihydrate) is representative for the lanthanides Er -Lu and the preparation of the terbium complex (as the pentahydrate) is representative for the lanthanides Sm - Ho, Yb, Lu (in the case of Sm, Eu and Ho the metal chloride was used). All the complexes prepared and their elemental analyses, mass spectral, infrared and NMR data are listed in Tables 1 - 4.
[Lu(H,ppma)~] [NO,],.3H20. The pH of an aqueous solution (4 mL) of H,ppma.3HCl.HzO (0.200 g, 0.257 mmol) and Lu(N03),.6Hz0 (0.060 g, 0.128 mmol) was raised to 2.0 using 3M NaOH. Colorless prisms deposited after 2 hours;
these prisms were filtered and dried under vacuum to yield 0.145 g (66.0 % ) . Yield for Yb 78.4%, Tm 50.2%, Er 53.0%.
[Tb(H,ppma)~][NO,],.5Hz0. An aqueous solution (0.7 mL) of H,ppma.3HC1.H20 (0.100 g, 0.128 mmol) was added to Tb(NO,),.5H20 (0.057 g, 0.128 mmol) in 0.7 mL of H20. Colorless hexagonal crystals deposited after 24 hours; these were filtered and dried under vacuum to yield 0.064 g (57.6 % ).
Yields for Lu 70. 5 % , Yb 73 .4 % , Ho 43 .2 % , Dy 50.1 % , Gd 63 .1 % , Eu 40. 3 %
, Sm 47.9 % .
NMR Measurements. The variable pH 'H NMR spectra of the H6tams and Hbtaps complexes were run in DZO with the pD values being measured by a Fisher Accumet 950 pH meter employing an Accumet Ag/AgCI combination microelectrode. The pD values were converted to pH by adding 0.40 to the observed reading. The "O NMR experiments with Dy(III) were recorded at 21°C, with a spectral window of 1000 Hz, a 90° pulse width of 18 ms, and an acquisition time of 0.256 s; this gave 512 data points. Two thousand transients were collected per spectrum. The "O linewidths for Hz0 were about 60 Hz. Concentrations employed ranged from 1 to 40 mM. The dysprosium induced shifts (DIS) were obtained from the observed shift by making a correction for the bulk magnetic susceptibility of the solution. Stock solutions were prepared from metal nitrates in DZO (H20) and the metal-ligand solutions were prepared by pipetting required amounts of stock solution and adjusting the pH with acid or base. In the equilibrium measurements, the ionic strength was controlled by addition of NaCI.
For the Ln - H,ppma (Ln = Yb, Lu) equilibrium constant studies using 3'P{H} NMR, conditions as described in a previous publication were used. Metal ion stock solutions (50 mM) were prepared from the hydrates of Lu(NO,), and Yb(N03)3.
All solutions contained a fixed amount of M'+ (25 mM) with the ligand concentration varied (R = [L]T/[M]T) as 0.25 < R < 4. Solutions were made up to a volume of 0.8 mL and the pH was adjusted to 1.5. The solutions were allowed to equilibrate for 48 hours prior to the spectra being collected. The respective peak integrals enabled a quantitative measurement (long delay times of 1.6 s were employed) of free ligand ([L]). The knowledge of [L] allowed n, the ratio of bound ligand to total metal to be calculated (n = ([L]T [L])/[M]T). A plot of n vs. [L] resulted in a curve from which the variables ~3, and X32 could be calculated using computer curve fitting software.
Potentiometric Equilibrium Measurements. The measurements were made at 25.0 t 0.1°, m = 0.16 M NaCI. The pKas of the ligands were checked whenever a different synthetic batch of ligand was used, and fresh ligand solutions were always employed (For Hbtaps: pKal = 1.7, pKa2 = 6.54, pKa3 = 7.78, pKa4 = 8.73, pKaS = 9.77, pKa6 = 11.24 and for Hbtams: pKal = 2.92, pKa2 = 6.56, pKa3 = 7.95, pKa4 = 8.91, pKaS = 9.81, pKa6 = 11.19).6 The lanthanide solutions were prepared by dilution of the appropriate atomic absorption standards.
Since the lanthanides do not hydrolyze below pH 6, the excess acid in the solutions could be obtained by titrating with standard NaOH and analyzing for the strong acid by the method of Gran.
The ratio of ligand to metal used was 1:2 < L:M < 4:1. Concentrations were in the range 0.5 - 2.5 mM. A minimum of five titrations were performed for each metal. The metal - Hbtaps and metal - Hbtams solutions were titrated to just beyond six equivalents NaOH /H~ ~,btams), because of slow hydrolysis beyond this point. Although complexation was rapid (1-3 min per point to give a stable pH
reading), care was taken to ensure that no trace hydrolysis or precipitation was occurring by monitoring up to 30 minutes for pH drift. The protonation constants for the lanthanide-ligand stability constants were determined by using the program BEST.1 Hbtams and Hbtaps, both reacted with Ln(III) to coordinate as hexadentate ligands, liberating six equivalents of acid per ligand. Typically 100 data points were collected with about 80-90 % of the points being in the buffer region of metal-ligand complexation and the remaining points in the strong acid region being used as a check of excess acid concentration.
X=ray Crystallographic Analyses of [C~H~LuN80,~ (NO,); 3HZO. Selected crystallographic data appear in Table 5. The final unit-cell parameters were obtained by least-squares on the setting angles for 25 reflections with 2 = 55.7-68.7 ° . The intensities of three standard reflections, measured every 200 reflections throughout the data collection, decayed linearly by 2.7 % . The data were processed and corrected for Lorentz and polarization effects, decay, and absorption (empirical, based on azimuthal scans).
The structure of [C~Ii~I,uNgO,z](NO,),~3Hz0 was solved by the Patterson method. The structure analysis was initiated in the centrosymmetric space group R c on the basis of the E statistics, this choice being confirmed by subsequent calcula-tions. The nitrate anions and water molecules were modeled as ( 1:1 ) disordered about a point of S6 symmetry. Because of thermal motion and near overlap of disordered components, the nitrate groups deviate from ideal geometry. Refinement of the structure in the noncentrosymmetric space group R3c failed to resolve the disorder.
All non-hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were fixed in calculated positions (N-H = 0.91 fir, C-H = 0.98 A, BH =
1.2 B~"~ ,~",). A correction for secondary extinction (Zacharaisen type) was applied, the final value of the extinction coefficient being 1.73(3) x 10-'. Neutral atom scattering factors for all atoms and anomalous dispersion corrections for the non-hydrogen atoms were taken from the International Tables for X Ray Crystallography.
Selected bond lengths and bond angles appear in Table 6. Complete tables of crystallographic data, final atomic coordinates and equivalent isotropic thermal parameters, anisotropic thermal parameters, bond lengths, bond angles, torsion angles, intermolecular contacts, and least-squares planes are included as Supporting Information.
Examples of Metal Complexes Comprising Bipodal Li~ands Synthesis of Lanthanide-xuta complexes. Three lanthanide complexes (La, Ho and Sm) were made and partially characterized. A general procedure for making the complexes is as follows: metal chloride (0.2 mmol) and Hsxuta ~ HCl (0.2 mmol) was dissolved in 7 mL water and the pH of the solution was raised to 6 -with 1 M KOH. Methanol was added until a precipitate formed, and this precipitate was collected and dried under vacuum to yield about 0.16 mmol (80 % ) of KZ[Ln(xuta)].
Preliminary studies of bis-{ [bis-(carboxymethyl)-amino]-methyl}-phosphinic acid (Hsxuta) with the lanthanides indicates that complex formation takes place at 1:1 metal to ligand ratio over a wide range of pH values. The lanthanide complexes are deliquescent.
The ligand ((HOZCCH2)zNCH2)2POZH (HSxuta) complexes metal ions at three sites and at intermediate pH levels, which increases the stability of the resulting complex.
As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this 2invention without departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims.
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Claims (11)
1. A process of chelating a metal ion which comprises complexing the metal ion with a ligand of the formula:
2. A process as claimed in claim 1 wherein the metal ion is selected from the group consisting of Tc, Re, the group 13 metals and rare earths.
3. A process of chelating Tc, Re, a trivalent metal ion of the group 13 metals and the rare earths which comprises complexing any one of Tc, Re, the group 13 metals, Al, Ga and In, and any one of the rare earths, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, with a ligand of the formula
4. A process as claimed in claim 3 wherein any one of the group 13 metals, Al, Ga and In is complexed with the ligand.
5. A process as claimed in claim 3 wherein any one of the lanthanide metals, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, is complexed with the ligand.
6. A chelate comprising a metal ion and a ligand of the formula:
7. A chelate as claimed in claim 6 wherein the metal ion is selected from the group consisting of Tc, Re, the group 13 metals and the rare earths.
8. A chelate comprising a complex of a trivalent metal ion of Tc, Re, the group 13 metals, Al, Ga and In, or the rare earths Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu and a ligand of the formula:
9. A chelate as claimed in claim 8 wherein the metal is selected from the group consisting of Al, Ga and In.
10. A chelate as claimed in claim 8 wherein the lanthanide is selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
11. A method of conducting diagnostic or therapeutic nuclear medicine which comprises using a metal complex of a bipodal ligand of the formula:
and a trivalent metal ion selected from the group consisting of Tc, Re, Al, Ga, In, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
and a trivalent metal ion selected from the group consisting of Tc, Re, Al, Ga, In, Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
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| CA 2246204 CA2246204A1 (en) | 1998-08-31 | 1998-08-31 | Bipodal ligand-metal ion chelates |
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| CA 2246204 CA2246204A1 (en) | 1998-08-31 | 1998-08-31 | Bipodal ligand-metal ion chelates |
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Cited By (1)
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| CN105037423A (en) * | 2015-07-23 | 2015-11-11 | 北京大学 | Effective rare earth complex luminescent material excited by shortwave ultraviolet |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105037423A (en) * | 2015-07-23 | 2015-11-11 | 北京大学 | Effective rare earth complex luminescent material excited by shortwave ultraviolet |
| CN105037423B (en) * | 2015-07-23 | 2017-12-12 | 北京大学 | A kind of efficient rare-earth complexes luminous material of short wave ultraviolet excitation |
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