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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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the plateau occurred at ∼10 mM Br– (Figure A.8, Supporting Information). A much higher Et4NI concentration (∼15 mM) was required to reach a plateau (∆δ = 1.5 ppm) (Figure A.9, Supporting Information). The interaction of halide ions with the exo-NH groups thus decreases in the order, Cl– Br– I– (Figure 2.10).

Of some interest, the two counteracting factors (H-bonding-induced electron density changes at the proton and anion H-bonding) influencing ∆δ of the endo-NH signal and the central NH signal in DMSO-d6 also explain the ∆δ of these NH signals in acetonitrile-d3. In particular, as shown in Figure A.9, Supporting Information, the endo-NH signal of [Re(CO)3(dipn)]+ in acetonitrile-d3 shifts upfield rather little (∆δ = -0.1 ppm) with added I– compared to the effect of Cl– (∆δ = -0.4 ppm). A small upfield shift could be caused by the downfield shifting effect of direct I– interaction with the endo-NH. However, I– has a very small direct effect. Thus, the smallness of the upfield shift undoubtedly arises from the weakness of the interaction of I– with the endo-NH group. The interaction of I– causes very little change in electron density at the endoNH proton. The results fully support our conclusions above.

Figure 2.10.

Effect of Cl–, Br–, and I– on ∆δ of the exo-NH signals of [Re(CO)3(dipn)]PF6 (1) in acetonitrile-d3 at 25 °C.

Interaction of the Paramagnetic Anion, [ReBr6]2–, with [Re(CO)3(dipn)]+. When [Bu4N]2[ReBr6] was added to a 5 mM solution of [Re(CO)3(dipn)]+ in acetonitrile-d3, upfield shift changes (negative ∆δ) for the NH signals were observed. At 1.65 mM [ReBr6]2–, ∆δ for the exo-NH (-3.6 ppm) was much greater than for the endo-NH (-1 ppm). However, during the titration, the exo-NH signal of 1 was often lost under CH2 multiplets (both from 1 and from [Bu4N]+ ions) in the 1H NMR spectral region of 1-3.5 ppm.

We reasoned that by exchanging the NH’s to ND’s to obtain [Re(CO)3(dipn-d5)]+, and by performing 2H NMR spectroscopy on the sample in normal solvent (CH3CN), we should be able to obtain exact ∆δ values throughout the titration. Accordingly, 2H NMR experiments were performed on [Re(CO)3(dipn-d5)]+ (5 mM, 600 µL) in CH3CN, and upfield ∆δ were noted upon each addition of aliquots of a 30 mM stock solution of [Bu4N]2[ReBr6] containing 5 mM [Re(CO)3(dipn-d5)]+. Figure 2.11 shows a plot of ∆δ vs. [ReBr6]2- concentration. At a final [ReBr6]2- concentration of 10 mM, no further upfield shift was observed for the exo-ND signal, and the maximum ∆δ was -6.1 ppm. For the endo-ND signal, the maximum ∆δ was only ca. -1.8 ppm. For the central ND signal, the ∆δ was negligible (0.03 ppm). Thus, the greater sensitivity of the exo-ND signal of 1 to the large paramagnetic [ReBr6]2- anion indicates clearly that this anion interacts with the exo-ND groups. The NMR data indicate strong interactions, and we estimate the ion-pairing constant to be greater than 1,000 M–1. However, accurate constants cannot be obtained. We further note that the large negative ∆δ values leave no doubt that [ReBr6]2- is acting as an outer-sphere paramagnetic shift reagent.

A preliminary investigation using [Re(CO)3(N,N-Me2dipn)]+ showed that the exo-NH group did not interact strongly with the [ReBr6]2- anion. This result is consistent with our interpretation of the nature of the anion interactions. Namely, we propose that the anions interact simultaneously with two exo-NH groups. Alternatively, the exo-NMe group could sterically prevent the anion from closely approaching the exo-NH.

Figure 2.11.

Effect of [ReBr6]2- on ∆δ of the ND signals of [Re(CO)3(dipn-d5)]PF6 in DMSO-d6 at 25 °C.

2.4 Conclusions The introduction of a third CH2 group, changing a dimethylene chain bridging the donor atoms in a 5-membered chelate ring to a trimethylene chain, does not significantly alter the exposure of the exo-NH groups of fac-[Re(CO)3L]n complexes to solvent. The exo-NH signal is relatively upfield for both 5- and 6-membered chelate rings. Adding the third CH2 group affects chiefly the ring conformation and the electron richness of the central NH group anchoring the two chelate rings in fac-[Re(CO)3L]n complexes.

The 6-membered chelate rings favor the chair conformation in both the solid and solution states. Specifically the most common conformations are designated as being endo-C. Thus, COSY data allow unambiguous assignment of the exo-NH and endo-NH signals, even when L is a symmetrical ligand. In contrast, the conformational interchange between the λ,λ and δ,δ conformations (or as we designate pucker, between the endo-C,exo-C and exo-C,endo-C conformations) precludes the use of COSY to assign NH2 signals when L is a symmetrical ligand with two 5-membered rings. However, at least for L in which there are no dangling groups or in which the dangling group is on the central N, the signals can be assigned by recognizing that the upfield NH signal of the NH2 group is the exo-NH signal.

The electron richness of the central NH group resulting from the third CH2 group leads to upfield shifts of the NH signal, with the upfield-shifting inductive effect increasing along the series: two 5-membered rings one 5- and one 6-membered ring two 6-membered rings.

Consistent with this trend, the interaction of the Cl– anion with this central NH group (as assessed with 1H NMR shift changes) decreases along this series, as would be expected from the increase in electron density at the proton. The latter observation reveals the utility of the use of the Cl– anion in combination with 1H NMR shift changes to probe the properties of the NH groups of complexes. Our work focuses on fac-[Re(CO)3L]n complexes of potential radiopharmaceutical utility. However, the anion probe method to assess the solvation around complexes and the variation in electron distribution should apply to other types of compounds, including complexes of other metals. Indeed, the [ReBr6]2– anion appears to be a promising Hbonding outer-sphere paramagnetic shift reagent, which complements the halide ions used in this study and earlier.24,32 The small upfield shifts observed for the endo-NH signal support the concept that two exo-NH groups simultaneously form H-bonds to the anion in the ion pair. These upfield endo-NH shifts are best understood as arising from the increase of electron density in the endo-N-H bond resulting from the interaction of the two exo-NH groups with the anion. Larger halide anions form H-bonds in the ion pair, but the interaction is weaker. The alteration of the electronic properties of L decreases with increasing halide size. Ion-pair stability decreases with halide size.

However, the dianionic charge of the large [ReBr6]2– anion overcomes this instability problem to a large extent, and the increased stability provides another reason that this anion should be explored more fully in future as an outer-sphere shift reagent.

2.5 References

1. He, H.; Lipowska, M.; Xu, X.; Taylor, A. T.; Marzilli, L. G. Inorg. Chem. 2007, 46, 3385Nieto, S.; Pérez, J.; Riera, L.; Miguel, D.; Golen, J. A.; Rheingold, A. L. Inorg. Chem. 2007, 46, 3407-3418.

3. Alberto, R.; Ortner, K.; Wheatley, N.; Schibli, R.; Schubiger, A. P. J. Am. Chem. Soc. 2001, 123, 3135-3136.

4. Alberto, R.; Schibli, R.; Egli, A.; Schubiger, A. P.; Abram, U.; Kaden, T. A. J. Am. Chem.

Soc. 1998, 120, 7987-7988.

5. He, H.; Lipowska, M.; Xu, X.; Taylor, A. T.; Carlone, M.; Marzilli, L. G. Inorg. Chem. 2005, 44, 5437-5446.

6. Schibli, R.; Schubiger, A. P. Eur. J. Nucl. Med. Mol. Imaging 2002, 29, 1529-1542.

7. Schibli, R.; Schwarzbach, R.; Alberto, R.; Ortner, K.; Schmalle, H.; Dumas, C.; Egli, A.;

Schubiger, A. P. Bioconjugate Chem. 2002, 13, 750-756.

8. Causey, P. W.; Besanger, T. R.; Schaffer, P.; Valliant, J. F. Inorg. Chem. 2008, 47, 8213Schibli, R.; Bella, R. L.; Alberto, R.; Garcia-Garayoa, E.; Ortner, K.; Abram, U.; Schubiger, A. P. Bioconjugate Chem. 2000, 11, 345-351.

10. Bartholomä, M.; Valliant, J.; Maresca, K. P.; Babich, J.; Zubieta, J. Chem. Commun.

(Cambridge, U.K.) 2009, 5, 493-512.

11. Maresca, K. P.; Kronauge, J. F.; Zubieta, J.; Babich, J. Inorg. Chem. Commun. 2007, 10, 1409-1412.

12. Storr, T.; Fisher, C. L.; Mikata, Y.; Yano, S.; Adam, M. J.; Orvig, C. Dalton Trans. 2005, 654-655.

13. Tzanopolou, S.; Pirmettis, I. C.; Patsis, G.; Paravatou-Petsotas, M.; Livaniou, E.;

Papadopoulos, M.; Pelecanou, M. J. Med. Chem. 2006, 49, 5408-5410.

14. Trejtnar, F.; Laznicek, M. Q. J. Nucl. Med. 2002, 46, 181-194.

15. Nosco, D. L.; Beaty-Nosco, J. A. Coord. Chem. Rev. 1999, 184, 91-12391.

16. Shikano, N.; Kanai, Y.; Kawai, K.; Ishikawa, N.; Endou, H. J. Nucl. Med. 2004, 45, 80-85.

17. Lipowska, M.; Marzilli, L. G.; Taylor, A. T. J. Nucl. Med. 2009, 50, 454-460.

18. Xia, J.; Wang, Y.; Li, G.; Yu, J.; Yin, D. J. Radioanal. Nucl. Chem. 2009, 279, 245-252.

19. Desbouis, D.; Struthers, H.; Spiwok, V.; Küster, T.; Schibli, R. J. Med. Chem. 2008, 51, 6689-6698.

20. Lipowska, M.; Hansen, L.; Xu, X.; Marzilli, P. A.; Taylor, A. T.; Marzilli, L. G. Inorg.

Chem. 2002, 41, 3032-3041.

21. Lipowska, M.; Cini, R.; Tamasi, G.; Xu, X.; Taylor, A. T.; Marzilli, L. G. Inorg. Chem.

2004, 43, 7774-7783.

22. Hansen, L.; Lipowska, M.; Meléndez, E.; Xu, X.; Hirota, S.; Taylor, A. T.; Marzilli, L. G.

Inorg. Chem. 1999, 38, 5351-5358.

23. Christoforou, A. M.; Fronczek, F. R.; Marzilli, P. A.; Marzilli, L. G. Inorg. Chem. 2007, 46, 6942-6949.

24. Christoforou, A. M.; Marzilli, P. A.; Fronczek, F. R.; Marzilli, L. G. Inorg. Chem. 2007, 46, 11173-11182.

25. Maverick, A. W.; Lord, M. D.; Yao, Q.; Henderson, L. J. Inorg. Chem. 1991, 30, 554-558.

26. Otwinowski, Z.; Minor, W. Macromolecular Crystallography, part A, Methods in Enzymology; New York Academic Press: New York, 1997; Vol. 276, pp. 307-326.

27. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, A64, 112-122.

28. Wieghardt, K.; Pomp, C.; Nuber, B.; Weiss, J. Inorg. Chem. 1986, 25, 1659-1661.

29. Suzuki, K.; Shimmura, N.; Thipyapong, K.; Uehara, T.; Akizawa, H.; Arano, Y. Inorg.

Chem. 2008, 47, 2593-2600.

30. DaCruz, M. F.; Zimmer, M. Inorg. Chem. 1998, 37, 366-368.

31. Bérces, A.; Whitfield, D. M.; Nukada, T. Tetrahedron 2001, 57, 477-491.

32. Perera, T.; Marzilli, P. A.; Fronczek, F. R.; Marzilli, L. G. Inorg. Chem. 2010, 49, 2123CHAPTER 3





3.1 Introduction Radiopharmaceuticals containing the fac-{99mTcI(CO)3}+ core hold promise for the development of new clinically useful imaging agents, fac-[99mTcI(CO)3L]n (L is a facially

–  –  –

among the most promising radionuclides for therapeutic applications.3 Many ligands having the ability to chelate facially with three donors such as N or a combination of N and O donors form

–  –  –

Although N donor groups are superior to the carboxylate O donor group in enhancing the ability of L to form fac-[99mTcI(CO)3L]n complexes,6 carboxylate groups generally have superior biological properties as radiopharmaceutical renal imaging agents.1,7 fac-[99mTcI(CO)3(NTA)]2NTAH3 = nitrilotriacetic acid) was recently reported to have pharmacodynamic renal clearance properties in rats good enough to merit testing in humans.8 This radiopharmaceutical is based on an aminopolycarboxylate ligand that can realistically form only one isomer. However, renal imaging agents with other target ligands, which usually have more N donors (such as polyaminopolycarboxylic acid ligands), form isomers under the normal aqueous conditions in which they are made.7,9 The presence of isomers complicates biomedical imaging.

*Reproduced with permission from American Chemical Society: Perera, T.; Marzilli, P. A.;

Fronczek, F. R.; Marzilli, L. G., “Several Novel N-Donor Tridentate Ligands Formed in Chemical Studies of New fac-Re(CO)3 Complexes Relevant to fac-99mTc(CO)3 Radiopharmaceuticals.

Attack of a Terminal Amine on Coordinated Acetonitrile,” Inorg. Chem. 2010, 49, 2123-2131.

Copyright 2010 American Chemical Society.

While much of our work has centered on examining preparations of fac-[M(CO)3L]n (M 99m Tc) complexes in water,1,7,8,10-14 for a number of reasons we wished to explore = Re or preparative chemistry in non-aqueous solvents. First, understanding the non-aqueous chemistry might allow us to prepare renal agents with only one or mainly one isomer. Second, isostructural technetium (radioactive imaging) and rhenium (fluorescence microscopic imaging) compounds allow correlation of images from in vivo and in vitro studies, respectively.4,15,16 However, the ligands needed to prepare fluorescent compounds are often only sparingly soluble in aqueous

–  –  –

water was not successful. Reasoning that reactions in organic solvents might be followed more easily in real time by NMR spectroscopy, we decided to evaluate fac-[Re(CO)3(CH3CN)3]+ as a soluble precursor for synthesizing fac-[Re(CO)3L]n compounds in organic solvents. We began our work with relatively simple tridentate amine ligands because complexes of several of these ligands had already been prepared in water.

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