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«A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of ...»

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fac-[Re(CO)3L]n complexes have provided a good model system for interpreting the nature of the analogous fac-[99mTc(CO)3L]n imaging agents formed in tracer level preparations.1,2 The convenient generation of the fac-[99mTc(CO)3(H2O)3]+ precursor3,4 and the straightforward preparation of the fac-[Re(CO)3(H2O)3]+ precursor5 have contributed toward developing new facmTc(CO)3L]n radiopharmaceuticals because fac-[Re(CO)3(H2O)3]+ allows the simulation of the synthesis of 99mTc complexes in aqueous media.2 Recently Re complexes have been emerging as radiopharmaceuticals in their own right, owing to the possibility of utilizing the {186/188Re(CO)3}+ core for therapeutic purposes.6,7 Additional evidence of the growing importance of this field is found in a recent report of a rapid and versatile microwave synthesis for preparing chelate complexes with the fac-{MI(CO)3}+ core (M = 99mTc, Re).8 fac-[99mTc(CO)3L]n complexes bearing tridentate ligands (L) are rather robust,6,9 and tridentate ligand systems bearing a dangling group with functional groups for conjugation to biomolecules or for directing the agent to a particular target are widely used.9-13 Ligands with carboxyl groups on dangling chains are normally evaluated in renal tracer development because the interaction of the renal receptor with the carboxyl group is important for clearance of small peptides.14-16 Tridentate ligands being investigated in bioconjugates or in tracers often have the *Reproduced with permission from American Chemical Society: Perera, T.; Marzilli, P. A.;

Fronczek, F. R.; Marzilli, L. G., “NH NMR Shifts of New, Structurally Characterized facRe(CO)3(polyamine)]n+ Complexes Probed via Outer-Sphere H-Bonding Interactions to Anions, Including the Paramagnetic [ReIVBr6]2- Anion,” Inorg. Chem. 2010, ASAP. Copyright 2010 American Chemical Society.

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chain dangling from the central N of diethylenetriamine (dien) are recognized as substrates by human thymidine kinase 1, a promising target for noninvasive imaging and therapy of malignant cells.19 A recent report describes fac-[188Re(CO)3((bis(2-pyridylmethyl)amino)ethylamine)]Br, a Re complex exhibiting promising biomedical properties and having a pyridyl-containing tridentate ligand with a dangling ethylamine group attached to the central N (Chart 2.1).18 Ligands named or used in this report are depicted in Chart 2.1. The H at the end of an abbreviation for a ligand name in Chart 2.1 or in the designation of a complex indicates the number of acidic hydrogens retained by the coordinated ligand, or in some cases, such as trenH (tris-(2-aminoethyl)amine), the H indicates that the coordinated ligand has become protonated.

Highly functionalized fac-[Re(CO)3L]n complexes are difficult to crystallize, and also the solution structures relevant to the likely structure of the tracer may differ from that in solution.

For example, dangling uncoordinated carboxyl groups (which are negatively charged and deprotonated at physiological pH) usually become neutral protonated groups in procedures employed to crystallize the complex.1,2,20-22 One goal of our study is to interpret how NMR spectra inform us about the solution structure of fac-[Re(CO)3L]n complexes. We first became aware that an unusually wide shift range exists for NH signals at amine groups terminating chelate rings (i.e., amines not anchoring two chelate rings) in fac-[Re(CO)3L]n complexes in a study of two fac-[Re(CO)3(ENDACH)] isomers (ENDACH2 ligand shown in Chart 2.1).21 For both isomers in the solid state, the coordinated carboxyl group is deprotonated, whereas the dangling carboxyl group is protonated. Two types of terminal NH’s were defined and unambiguously identified through the crystallography of the two isomers. In one isomer, the terminal amine has an endo-NH proton (defined as the proton projecting toward the carbonyl ligands, Figure 2.1) with a normal relatively downfield shift (5.84 ppm, DMSO-d6) for a terminal secondary amine NH signal. In the other isomer, this amine has an exo-NH proton (defined as the proton projecting away from the carbonyl ligands, Figure 2.1).21 The signal of this terminal secondary amine exo-NH proton was observed at a rather upfield position (5.36 ppm, DMSO-d6).

Chart 2.1.

Ligands used or mentioned in this study Figure 2.1.

Designation of endo and exo protons in 5-membered (left) and 6-membered (right) rings, as illustrated based on the molecular structure of [Re(CO)3(aepn)]PF6. The exo-NH or exoCH protons point away from the carbonyl ligands and the endo-NH or endo-CH protons point toward the carbonyl ligands.

In later studies,1,5,23 we found a relatively wide range of NH shifts also for terminal primary amine groups in fac-[Re(CO)3L]+ complexes.1,23 When L = lanthionine isomers as the tridentate ligand (LANH2, Chart 2.1), the fac-[Re(CO)3(LAN)]– isomers exhibited NH signals differing in shift, but the shift range was not readily understood.1 For some primary amine groups the two NH signals were well dispersed, whereas for others the shifts of both NH signals were similar.1 Because the two deprotonated dangling carboxyl groups of the fac-[Re(CO)3(LAN)]– complex could be influencing shift, we examined fac-[Re(CO)3L]+ complexes with such minimal prototypical ligands as dien or simple dien-related ligands (e.g., daes, Chart 2.1) to establish baseline chemical shift characteristics that define NMR parameters for fac-[Re(CO)3L]n complexes.24 For the prototypical fac-[Re(CO)3L]+ complexes, with L lacking dangling groups and forming two 5-membered rings, downfield and upfield NH signals were observed and assigned to endo-NH and exo-NH protons, respectively.24 We hypothesized that the shift differences might be attributable in part to the lower exposure to solvent of the exo-NH protons compared to the endo-NH protons. We reasoned that the chelate rings forming the face defined by L might provide a steric barrier that inhibits full access of the polyatomic solvent molecules to the exoNH. As a result, the solvent cannot approach the exo-NH closely enough to allow formation of strong solvent to NH H-bonding interactions (an interaction causing downfield shifts).24 Therefore, we evaluated the interaction of the small monoatomic Cl– anion with these prototypical complexes.24 We reasoned that the Cl– anion would be attracted to the cationic complex, leading to an ion pair with the Cl– anion H-bonded preferentially to the poorly solvated exo-NH groups. This interaction caused larger downfield shifts for the exo-NH signal than for the endo-NH signal, consistent with our hypothesis that solvent molecules are too large to access the exo-NH groups well. The extent of solvent accessibility to exo-NH groups might be altered by dangling groups on the ligands, by replacement of one of the groups with other donor types, by chelate ring size, as well as by other possible factors.





In the present study, we investigate fac-[Re(CO)3L]n+ complexes bearing polyamine ligands having 6-membered chelate rings to determine if some of the same unusual NH shifts are present in the 1H NMR spectra of these compounds. Also, we test further our proposal that at least a significant factor influencing shift is solvent exposure by assessing the interaction of anions of increasing size along the series: Cl–, Br–, and I–. We also evaluated the large paramagnetic ReIV anion, [ReBr6]2-. This series of studies was designed to test the solvent exposure hypothesis that small species are expected to access the sterically hindered face of the octahedron defined by the tridentate ligand better than larger anions. Two-dimensional NMR NH signal assignment is more straightforward for fac-[Re(CO)3L]n+ complexes bearing polyamine ligands having two 6-membered chelate rings than for fac-[Re(CO)3L]n+ complexes bearing polyamine ligands having 5-membered chelate rings because ring pucker in the latter type of compounds is usually very fluxional and different for the two chelate rings.24 From now on, we omit the fac- designation when discussing specific compounds because all the new compounds have this geometry.

2.2 Experimental Section

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methyldipropylamine (N′-Medipn), N,N-dimethyldipropylenetriamine (N,N-Me2dipn), tris-(3aminopropyl)amine (trpn), 1,4,7-triazacyclononane (tacn), and Re2(CO)10 from Aldrich were used as received. [Re(CO)3(H2O)3]OTf (OTf = trifluoromethanesulfonate) and [Bu4N]2[ReBr6] were prepared by known methods.5,25 NMR Measurements. 1H (400 MHz) and 2H NMR (unlocked) spectra were recorded on Bruker spectrometers. Peak positions are relative to TMS by using TMS or in some cases solvent residual peak, referenced in turn to TMS. NMR data were processed with TopSpin and Mestre-C software.

X-ray Data Collection and Structure Determination. Intensity data were collected at 90.0(5) K on a Nonius Kappa CCD diffractometer fitted with an Oxford Cryostream cooler and graphite-monochromated MoKα (λ = 0.71073 Å) radiation. Data reduction included absorption corrections by the multi-scan method, with HKL SCALEPACK.26 All X-ray structures were determined by direct methods and difference Fourier techniques and refined by full-matrix least squares, using SHELXL97.27 All non-hydrogen atoms were refined anisotropically, except for those in the 6-membered chelate rings of 5, which were disordered into two conformations. Except for those on the water molecule in 1, all H atoms were visible in difference maps. H atoms on C and N were placed in idealized positions, except for the NH hydrogen atoms in 2, 4, and 6. A torsional parameter was refined for each methyl group.

Compound 1 has three independent Re complexes in the asymmetric unit, two of which have disordered (CH2)3 groups. Compound 3 has two formula units in the asymmetric unit. Compound 7 crystallizes in a chiral conformation as an enantiopure crystal, as evidenced by Flack parameter x = 0.014(6).

Synthesis of fac-[Re(CO)3L]PF6 and fac-[Re(CO)3L]BF4 Complexes. An aqueous solution of [Re(CO)3(H2O)3]OTf (5 mL, 0.1 mmol) was treated with the ligands, L (0.1 mmol).

The pH was adjusted to ∼6 (3 mL of methanol was added to dissolve any precipitate that formed), and the clear reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, treated with solid NaPF6 or NaBF4 (∼15 mg), and then left undisturbed. X-ray quality crystals formed within 2-3 days. Specific procedures are detailed below.

[Re(CO)3(dipn)]BF4 (1). Treatment of [Re(CO)3(H2O)3]OTf with dipn (15 µL) as described above afforded [Re(CO)3(dipn)]BF4 as colorless crystals (17 mg, 35% yield) after the addition of NaBF4. The product was characterized by single-crystal X-ray diffraction. 1H NMR spectrum (ppm) in DMSO-d6: 6.00 (b, 1H, NH), 5.23 (d, 2H, NH), 3.79 (b, 2H, NH), 3.20 (m, 2H, CH2), 2.90 (m, 2H, CH2), 2.68 (m, 2H, CH2), 2.62 (m, 2H, CH2), 1.88 (m, 2H, CH2), 1.68 (m, 2H, CH2). [Re(CO)3(dipn)]PF6. Treatment of [Re(CO)3(H2O)3]OTf with dipn as described above afforded [Re(CO)3(dipn)]PF6 as colorless crystals (36 mg, 66% yield) after the addition of NaPF6. The product could not be characterized by single-crystal X-ray diffraction because of twinning. 1H NMR spectrum (ppm) in DMSO-d6: identical to that of [Re(CO)3(dipn)]BF4.

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µL) as described above afforded [Re(CO)3(N′-Medipn)]PF6 as colorless crystals (18 mg, 32% yield) after the addition of NaPF6. The product was characterized by single-crystal X-ray diffraction. 1H NMR spectrum (ppm) in DMSO-d6: 5.30 (d, 2H, NH), 3.80 (t, 2H, NH), 3.20 (m, 2H, CH2), 3.02 (m, 2H, CH2), 2.98 (s, 3H, CH3), 2.65 (m, 4H, CH2), 1.90 (m, 2H, CH2), 1.88 (m, 2H, CH2).

[Re(CO)3(N,N-Me2dipn)]BF4 (3). Treatment of [Re(CO)3(H2O)3]OTf with N,N-Me2dipn (18 µL) as described above afforded [Re(CO)3(N,N-Me2dipn)]BF4 as colorless crystals (29 mg, 56% yield) after the addition of NaBF4. The product was characterized by single-crystal X-ray diffraction. 1H NMR spectrum (ppm) in DMSO-d6: 6.34 (s, 1H, NH), 5.53 (d, 1H, NH), 3.78 (t, 1H, NH), 3.24 (m, 1H, CH2), 3.01 (s, 3H, CH3), 2.90 (m, 3H, CH2), 2.80 (m, 1H, CH2), 2.71 (m, 3H, CH2), 2.62 (s, 3H, CH3), 1.94 (m, 1H, CH2), 1.86 (m, 1H, CH2), 1.62 (m, 2H, CH2).

[Re(CO)3(trenH)](PF6)2 (4). Treatment of [Re(CO)3(H2O)3]OTf with tren (16 µL) as described above afforded [Re(CO)3(trenH)](PF6)2 as colorless crystals (34 mg, 47% yield) after the addition of NaPF6. The product was characterized by single-crystal X-ray diffraction. 1H NMR spectrum (ppm) in DMSO-d6: 7.70 (b, 3H, NH), 5.62 (b, 2H, NH), 4.22 (b, 2H, NH), 3.57 (m, 2H, CH2), 3.18 (m, 2H, CH2), 3.09 (m, 2H, CH2), 2.91 (m, 6H, CH2).

[Re(CO)3(trpnH)](PF6)2 (5). Treatment of [Re(CO)3(H2O)3]OTf with trpn (20 µL) as described above afforded [Re(CO)3(trpnH)](PF6)2 as colorless crystals (34 mg, 45% yield) after the addition of NaPF6. The product was characterized by single-crystal X-ray diffraction. 1H NMR spectrum (ppm) in DMSO-d6: 7.69 (b, 3H, NH), 5.39 (b, 2H, NH), 3.72 (b, 2H, NH), 3.10 (m, 4H, CH2), 2.85 (m, 4H, CH2), 2.75 (m, 4H, CH2), 1.96 (m, 6H, CH2).

[Re(CO)3(aepn)]PF6 (6). Treatment of [Re(CO)3(H2O)3]OTf with aepn (13 µL) as described above afforded [Re(CO)3(aepn)]PF6 as colorless crystals (30 mg, 56% yield) after the addition of NaPF6. The product was characterized by single-crystal X-ray diffraction. 1H NMR spectrum (ppm) in DMSO-d6: 6.47 (b, 1H, NH), 5.50 (d, 1H, NH), 5.24 (d, 1H, NH), 4.08 (b, 1H, NH), 3.50 (t, 1H, NH), 3.25 (m, 1H, CH2), 3.04 (m, 1H, CH2), 2.97 (m, 1H, CH2), 2.63 (m, 3H, CH2), 2.57 (m, 1H, CH2), 2.43 (m, 1H, CH2), 1.94 (m, 1H, CH2), 1.74 (m, 1H, CH2).

[Re(CO)3(tacn)]PF6 (7). Treatment of [Re(CO)3(H2O)3]OTf with tacn (13 mg) as described above afforded [Re(CO)3(tacn)]PF6 as colorless crystals (30 mg, 55% yield) after the addition of NaPF6. The product was characterized by single-crystal X-ray diffraction. 1H NMR spectrum (ppm) in DMSO-d6: 7.06 (b, 3H, NH), 2.96 (m, 6H, CH2), 2.88 (m, 6H, CH2).

Cl– Titration of [Re(CO)3L]PF6 Complexes. A 5 mM solution of the desired facRe(CO)3L]PF6 complex in DMSO-d6 or acetonitrile-d3 (600 µL) was treated with increasing amounts of Et4NCl (1 to 125 mM), and the solution was monitored by 1H NMR spectroscopy after each Cl– aliquot was added. All Et4NCl stock solutions were prepared by using a 5 mM solution of the complex to keep the complex concentration constant throughout the titration.

Similar experiments were performed with [Re(CO)3(dipn)]PF6 in acetonitrile-d3 by using Et4NBr (1 to 125 mM) and Et4NI (1 to 50 mM, owing to low solubility).



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