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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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16. Chin, C. S.; Chong, D.; Lee, S.; Jeong, H.; Won, G.; Do, Y.; Park, Y. J. Organometallics 2000, 19, 638-648.

17. Bianucci, A. M.; Demartin, F.; Manassero, M.; Masciocchi, N.; Ganadu, M. L.; Naldini, L.;

Panzanelli, A. Inorg. Chim. Acta 1991, 182, 197-204.

18. Bokach, N. A.; Kukushkin, V. Y.; Kuznetsov, M. L.; Garnovskii, D. A.; Natile, G.;

Pombeiro, A. J. L. Inorg. Chem. 2002, 41, 2041-2053.

19. Rouschias, G.; Wilkinson, G. J. Chem. Soc. A 1968, 489-496.

20. Kunz, P. C.; Kurz, P.; Spingler, B.; Alberto, R. Z. Anorg. Allg. Chem. 2007, 633, 2753-2756.

21. Schmidt, S. P.; Trogler, W. C.; Basolo, F. Inorg. Synth. 1990, 28, 160-165.

22. Edwards, D. A.; Marshalsea, J. J. Organomet. Chem. 1977, 131, 73-91.

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

24. Sheldrick, G. M. "SHELXL97, Program for Crystal Structure Solution and Refinement," University of Gottingen: Gottingen, Germany, 1997.

25. Chan, L. Y. Y.; Isaacs, E. E.; Graham, W. A. G. Can. J. Chem. 1977, 55.

26. Caspar, J. V.; Meyer, T. J. J. Phys. Chem. 1983, 87, 952-957.

27. Hayashi, Y.; Kita, S.; Brunschwig, B. S.; Fujita, E. J. Am. Chem. Soc. 2003, 125, 11976Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. J. Chem.

Soc. Perkin Trans. 2 1987, S1-S19.

29. Perera, T.; Fronczek, F. R.; Marzilli, P. A.; Marzilli, L. G., Inorg. Chem. DOI:


30. Hazell, A.; Simenson, O.; Wernberg, O. Acta Crystallogr., Sect. C 1986, C42, 1707-1711.

31. Hazell, A. Polyhedron 2004, 23, 2081-2083.

32. Maheshwari, V.; Carlone, M.; Fronczek, F. R.; Marzilli, L. G. Acta Crystallogr., Sect. B 2007, B63, 603-611.

33. Connick, W. B.; Henling, L. M.; Marsh, R. E.; Gray, H. B. Inorg. Chem. 1996, 35, 6261Christoforou, A. M.; Marzilli, P. A.; Fronczek, F. R.; Marzilli, L. G. Inorg. Chem. 2007, 46, 11173-11182.

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attention in the past two decades.1-6 Many factors have contributed to this interest, including the convenient generation of the fac-[99mTc(CO)3(H2O)3]+ precursor7,8 and the utility of facRe(CO)3L]n analogues (L is a facially coordinated tridentate ligand) to serve as model systems allowing the chemistry of the short-lived radioactive fac-[99mTc(CO)3L]n imaging agents to be

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therapeutic applications.12 Tridentate ligands form stable and kinetically inert complexes containing the {MI(CO)3}+ core (M = 99mTc, Re).12 Luminescent probes based on Re(I) are particularly useful for studying biological processes by virtue of their long lifetime, polarized emission, and large Stokes shift.13-15 Recently fac-Re(CO)3 complexes bearing di(2-picolyl)lamine (N(H)dpa) derivatives have generated much interest in biomedical research.13,16,17 In naming ligands in this article, the N designates the central (sp3) nitrogen, with the substituent replacing the NH proton. Zubieta and co-workers have based some of their work relating to the bifunctional chelate design for {MI(CO)3}+ (M = 99mTc, Re) on the tridentate ligand, N(H)dpa,13,18 in which the amine nitrogen provides a site for tethering additional functional groups. A 188Re complex containing the N(aminoethyl)dpa ligand

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were synthesized in an effort to develop stable carbohydrate-appended imaging and therapeutic agents.16 Also fac-[99mTc(CO)3(N(3,5-dimethoxybenzyl)dpa)]+ has been developed and evaluated for cardiac uptake.19 Highly lipophilic cations are thought to be required for high uptake and retention in the myocardium;19 the N(H)dpa moiety was chosen because it allows the lipophilicity to be modulated through easy derivation of the central N and because the size and lipophilicity of the ligands could be varied without the formation of isomers.19 The fact that no new 99mTc imaging agent has received FDA approval for over a decade13 clearly indicates the need for exploring novel ligands that could impart superior characteristics into such agents. In designing ligands with new methods of conjugation, it is important to consider and take advantage of geometric constraints. As an example, in designing tetradentate ligands to form octahedral cobalt complexes that adopt a specific geometry, the NSNN donor set was used,20 taking advantage of the fact that S atoms act as internal donor atoms with a known stereochemical preference to bind pyramidally (i.e., enforce a facial coordination mode).21 Evaluating literature examples, we found that although the usual situation is that sulfonamide N atoms do not coordinate metals unless they are deprotonated,22-25 a few examples exist in which a tertiary sulfonamide is coordinated to a metal, albeit in cylic ligands.24,26-28 Parallelling this observation are cases in which tertiary sulfonamide groups do not bind metals; the tertiary sulfonamide nitrogen did not bind metals in porphyrins containing only tertiary sulfonamide groups29 and in square planar Pd complexes.30,31 Such coordination ordinarily would require that the N permits meridional coordination.

In this study, we report on the synthesis of new ligands bearing central sulfonyl groups on the dpa unit (N(SO2R)dpa, R = Me, tmb, and 5-(dimethylamino)-naphthalene; see Figure 6.1 for ligands and their abbreviations) and their fac-[Re(CO)3L]+ complexes. As mentioned, the study

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ligands L (novel ligands bearing central sulfonyl groups, and two pyridine rings) afforded facRe(CO)3L]+ complexes bearing a tertiary sulfonamide linkage. This study is the first structural characterization of a tertiary neutral sulfonamide to be linked to the fac-Re(CO)3 core. It is also the first such study of open-chain sulfonamides with any metal.

Figure 6.1.

Ligands used in this study: N,N-di(2-picolyl)methanesulfonamide (N(SO2Me)dpa), N,N-di(2-picolyl)-2,4,6-trimethylbenzenesulfonamide (N(SO2tmb)dpa), N,N-di(2-picolyl)-5dimethylamino)-naphthalene-1-sulfonamide (N(dansyl)dpa).

We test our conjugation method by utilizing a tetraarylporphyrin (T(N(SO2C6H4)dpa)P) which contains four peripheral dpa moieties linked to the porphyrin via a tertiary sulfonamide (Scheme 6.1) and by evaluating the formation of a 1:4 porphyrin:Re adduct. The results demonstrate that the tertiary sulfonamide linkage may be utilized to tether biologically important molecules and propose that it may be extended to the {99mTcI(CO)3}+ core. From now on, we omit the fac- designation when discussing specific compounds because all the new compounds have this geometry.

Scheme 6.1.

Synthesis of T(NSO2C6H4)dpa)P

6.2 Experimental Section

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trimethylbenzenesulfonyl chloride (tmbSO2Cl), 5-(dimethylamino)naphthalene-1-sulfonyl chloride (dansyl chloride), di(2-picolyl)lamine (N(H)dpa), and Re2(CO)10 were used as received from Aldrich. [Re(CO)3(H2O)3]OTf (OTf = trifluoromethanesulfonate) was prepared by a known method.32 [Re(CO)3(CH3CN)3]BF4 and meso-tetra-(4-chlorosulfonylphenyl)porphryin (TClSO2PP) were synthesized as described elsewhere,33,34 and the 1H NMR chemical shifts

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spectrometer. Peak positions are relative to tetramethylsilane (TMS) or solvent residual peak with TMS as reference. All NMR data were processed with TopSpin and Mestre-C software.

X-ray Data Collection and Structure Determination. Single crystals were placed in a cooled nitrogen gas stream at 90 K on a Nonius Kappa CCD diffractometer fitted with an Oxford Cryostream cooler with graphite-monochromated Mo Kα (0.71073 Å) radiation. Data reduction included absorption corrections by the multi-scan method, with HKL SCALEPACK.35 All X-ray structures were determined by direct methods and difference Fourier techniques and refined by full-matrix least squares by using SHELXL97.36 All non-hydrogen atoms were refined anisotropically. All H atoms were visible in difference maps, but were placed in idealized positions. A torsional parameter was refined for each methyl group.

Synthesis of [Re(CO)3L]PF6 and [Re(CO)3L]BF4 Complexes. The following general procedure was employed to obtain the N(SO2R)dpa ligands. A solution of the sulfonyl chloride (5 mmol) in 25 mL of dioxane was added dropwise over a period of 2 h to a solution of N(H)dpa, (10 mmol) in 100 mL of dioxane at 20 ºC. The reaction mixture was stirred at room temperature for 24 h and then filtered to remove any precipitate before the dioxane was completely removed by rotary evaporation. Water (30 mL) was added to the resulting oil, and the product was extracted into CH2Cl2 (2 × 25 mL). The CH2Cl2 portions were combined, washed with water (2 × 25 mL), and taken to dryness to yield an oil, which was used to synthesize [Re(CO)3L]PF6 and [Re(CO)3L]BF4 in the general procedure outlined here. An aqueous solution of the ligand (0.1 mmol in 2 mL) was treated with an aqueous solution of [Re(CO)3(H2O)3]+ (0.1 mmol in 3 mL).

Methanol (2-3 mL) was added to dissolve any precipitate that formed, and the clear reaction mixture was heated at reflux for 12 h. A slight excess of NaPF6 or NaBF4 was added to the clear solution, and the resulting precipitate was collected on a filter, washed with water, and air dried.

(If the pH of the final reaction mixture was below 6, it was adjusted to 7 before adding NaPF6;

for N(SO2tmb)dpa and N(dansyl)dpa, methanol (∼1 mL) was used initially to dissolve the ligand).

[Re(CO)3(N(SO2Me)dpa)]PF6 (1). The general method described above, with MeSO2Cl (0.39 mL) and N(H)dpa (1.80 mL), yielded the crude N(SO2Me)dpa ligand as a deep red oil (1.40 g, 76% yield). 1H NMR signals (ppm) in DMSO-d6: 8.50 (s, 2H, H6/6′), 7.75 (t, 2H, H4/4′), 7.34 (d, 2H, H3/3′), 7.27 (t, 2H, H5/5′), 4.48 (s, 4H, CH2), 3.11 (s, 3H, CH3). The general method described, with N(SO2Me)dpa (28 mg) and [Re(CO)3(H2O)3]+ (0.1 mmol), afforded [Re(CO)3(N(SO2Me)dpa)]PF6 as a white precipitate (38 mg, 54% yield) after the addition of NaPF6 (∼15 mg). Slow evaporation of a solution of the compound in acetone produced colorless, needle-like crystals that were characterized by single-crystal X-ray crystallography. 1H NMR signals (ppm) in DMSO-d6: 8.89 (d, 2H, H6/6′), 8.09 (t, 2H, H4/4′), 7.57 (d, 2H, H3/3′), 7.53 (t, 2H, H5/5′), 5.44 (d, 2H, CH2), 5.13 (d, 2H, CH2), 3.87 (s, 3H, CH3).

[Re(CO)3(N(SO2tmb)dpa)]PF6 (2). The general method described above, with tmbSO2Cl (1.10 g) and N(H)dpa (1.80 mL), yielded N(SO2tmb)dpa as a pale orange oil (1.75 g, 92% yield). 1H NMR signals (ppm) in DMSO-d6: 8.43 (s, 2H, H6/6′), 7.65 (t, 2H, H4/4′), 7.22 (t, 2H, H5/5′), 7.09 (d, 2H, H3/3′), 6.97 (s, 2H), 4.54 (s, 4H, CH2), 2.53 ( s, 6H, CH3), 2.23 (s, 3H, CH3). The general method above, with N(SO2tmb)dpa (38 mg) and [Re(CO)3(H2O)3]+ (0.1 mmol), afforded [Re(CO)3(N(SO2tmb)dpa)]PF6 as a white precipitate (51 mg, 64% yield) after the addition of NaPF6 (∼15 mg). Slow evaporation of a solution of the compound in chloroform produced colorless, block-like crystals that were characterized by single-crystal X-ray crystallography. 1H NMR signals (ppm) in DMSO-d6: 8.90 (d, 2H, H6/6′), 8.05 (t, 2H, H4/4′), 7.64 (d, 2H, H3/3′), 7.49 (t, 2H, H5/5′), 7.46 (s, 2H), 5.22 (d, 2H, CH2), 4.53 (d, 2H, CH2), 2.78 (s, 6H, CH3), 2.43 (s, 3H, CH3).

[Re(CO)3(N(dansyl)dpa)]BF4 (3). The general method described above, with dansyl chloride (1.42 g) and N(H)dpa (1.8 mL), yielded N(dansyl)dpa as a pale orange oil (1.96 g, 91% yield). 1H NMR signals (ppm) in DMSO-d6: 8.44 (d, 1H), 8.37 (d, 2H), 8.20 (d, 1H), 8.16 (d, 1H), 7.58 (t, 2H), 7.54 (m, 2H), 7.23 (d, 1H), 7.18 (t, 2H), 7.12(d, 2H), 4.72 (s, 4H, CH2), 2.82 (s, 6H, CH3). The general method described, with N(dansyl)dpa (43 mg) and [Re(CO)3(H2O)3]+ (0.1 mmol), afforded [Re(CO)3(N(dansyl)dpa)]BF4 as yellow block-like crystals (38 mg, 44% yield) after the addition of NaBF4 (∼15 mg). The product was characterized by single-crystal Xray crystallography. 1H NMR signals (ppm) in DMSO-d6: 8.90 (m, 3H), 8.71 (d, 1H), 8.58 (d, 1H), 7.98 (t, 2H), 7.92 (t, 1H), 7.78 (t, 1H), 7.47 (t, 2H), 7.42 (d, 2H), 7.39 (d, 1H), 5.64 (d, 2H), 4.53 (d, 2H, CH2), 2.91 (s, 6H, CH3).

T(N(SO2C6H4)dpa)P. A solution of TClSO2PP (0.4 g, 0.39 mmol) in CH2Cl2 (50 mL) was treated with N(H)dpa (3.7 mL, 1.98 mmol), and the reaction mixture was stirred at room temperature for 24 h. Impurities in this mixture were then extracted with water (3 × 25 mL); the organic layer was dried over anhydrous Na2SO4 and the solvent removed under vacuum. The purple residue was crystallized from CH2Cl2/hexane and washed with hexane (0.32 g, 49 % yield). 1H NMR signals (ppm) in DMSO-d6: 8.87 (s, 8H, βH), 8.55 (d, 8H, H6/6′), 8.37 (d, 8H, oH), 8.24 (d, 8H, mH), 7.83 (t, 8H, H4/4′), 7.49 (d, 8H, H3/3′), 7.34 (t, 8H, H5/5′), 4.90 (s, 16H, CH2), -2.96 (s, 2H, NH). ESI-MS(m/z): [M + H]+ = 1660.4881, [M + 2H]+2 = 830.7465. Calcd for [M + H]+ = 1660.4886, [M + 2H]+2 = 830.7443.

[{Re(CO)3}4T(N(SO2C6H4)dpa)P](BF4)4 (4). [Re(CO)3(CH3CN)3]BF4 (28 mg, 0.058 mmol) was added to a solution of T(N(SO2C6H4)dpa)P (20 mg, 0.012 mmol) in a mixture of chloroform/acetone (25 mL/5 mL). The reaction mixture was heated at reflux for 16 h and reduced to dryness by rotary evaporation. The resulting maroon residue was quickly washed with CH2Cl2, dissolved in acetone, and the resultant solution layered with hexane to give a maroon precipitate (15 mg, 40% yield). 1H NMR signals (ppm) in DMSO-d6: 9.19 (s, 8H, βH), 9.01 (d, 8H, H6/6′), 8.84 (s, 16H, o,mH), 8.14 (t, 8H, H4/4′), 7.71 (d, 8H, H3/3′), 7.58 (t, 8H, H5/5′), 5.98 (d, 8H, CH2), 4.97 (d, 8H, CH2), -2.81 (s, 2H, NH).

6.3 Results and Discussion Synthesis of N(SO2R)dpa and [Re(CO)3(N(SO2R)dpa)]PF6. We have synthesized potential tridentate ligands bearing MeSO2, tmbSO2, and dansyl groups at the central N (Figure 6.1) by coupling N(H)dpa with the desired sulfonyl chloride. The ligands were obtained in good yield and quite pure, as indicated by NMR spectral data (Experimental Section). NMR spectra of the new ligands are given in Supporting Information and show no N(H)dpa left in sample. A [Re(CO)3(H2O)3]OTf aqueous solution32 was used to prepare complexes 1-3 (Scheme 6.2).

Scheme 6.2.

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