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Tricarbonylrhenium(I) complexes with anionic ligands containing S and O donor atoms – potential radiopharmaceutical precursors
Polyhedron 29 (2010) 634–638
Contents lists available at ScienceDirect
Polyhedron journal homepage: www.elsevier.com/locate/poly
Tricarbonylrhenium(I) complexes with anionic ligands containing S and O donor atoms – potential radiopharmaceutical precursors Leon Fuks, Ewa Gniazdowska, Przemysław Koz´min´ski * Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland
a r t i c l e
i n f o
Article history: Available online 9 September 2009 Keywords: Tricarbonylrhenium(I) Thiosalicylic derivatives Molecular structure X-ray diffraction IR spectra Quantum chemical calculations
a b s t r a c t Equilibrium geometry of tricarbonylrhenium(I) thiosalicylate and of methylthiosalicylate has been determined by the X-ray diffraction studies as well as calculated by the semiempirical method using the PM3 functional basis set. Infrared spectra of the species have also been studied in the 4000800 cm1 range of wavenumbers. The experimental and theoretical data are in satisfactory agreement. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Radionuclides are used in numerous medicinal diagnostic and/ or therapeutic procedures. Such techniques have increased the demand for new complexes containing carrier-free radionuclides having reasonable half lives and proper energy of radiation. Rhenium-188 (Re-188), a decay product of tungsten-188 (W-188), is one of the promising therapeutic radionuclides. This radionuclide has favorable nuclear properties: half-life time of 16.98 h, beta radiation of 2.12 MeV accompanied by gamma radiation (Ec = 155 keV, 15% of total emitted energy), which make it ideal for imaging of tumors using gamma cameras [1]. Because the radionuclide is available in nuclear medicine clinics at a reasonably low price from the W-188/Re-188 generator [2] it is ideal for radiotherapeutic applications. For instance, after labelling the monoclonal antibodies with Re-188 the obtained compounds are used for targeting tumor cells. Another radionuclide of rhenium produced in nuclear reactors, the Re-186 nuclide (t1/2 = 89.3 h, Eb = 1.07 MeV, 8% of gamma emission with Ec = 137 keV [3]), should be mentioned as one among only three radionuclides approved for treatment of pain [4]. The same radionuclide, when carried by liposomes into the tumor intraoperative remnants of head and neck squamous cell carcinoma, may play a role in the management of positive surgical margins with minimal side-effects [5]. In 1995 Schubiger et al. have presented for the first time one-step synthesis of the fac-Re(CO)3(OH2)3+ complex by direct reduction of ReO4 in aqueous solution with sodium borohydride * Corresponding author. Tel.: +48 22 504 1011. E-mail addresses: [email protected], (P. Koz´min´ski).
[email protected]
0277-5387/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.poly.2009.08.030
in the presence of carbon monoxide [6]. At present, tricarbonylrhenium(I) complexes (of the octahedral or tetragonal bipyramide structure) seem to be candidates for design of new radiopharmaceuticals. Water-soluble radiopharmaceutical precursor, Re(CO)3(OH2)3+, is stable in aqueous solutions over the broad pH range (pH 2–12) for several hours. Three water molecules coordinated to the highly inert fac-Re(CO)3+ core can be easily replaced by various functional groups, such as amines, thioethers, thiols and phosphines. This can be done by using one tridentate ligand (the so-called ‘‘3+0” approach [6]) or one bidentate and one monodentate ligand (‘‘2+1” mixed-ligand complexes [7–9]). Because of small size and small charge of the fac-Re(CO)3+ group, it does not influence significantly biological properties of even the smallest biomolecules used in the synthesis of radiopharmaceuticals. This work comprises the synthesis, chemical, spectroscopic and quantum calculation (QC) studies on the tricarbonylrhenium(I) species complexed either by thiosalicylic acid (2-mercaptobenzoic acid, 2-sulfanylbenzoic acid) or by methyl thiosalicylate (methyl 2-mercaptobenzoate). All experiments were performed on the milligram scale using the non-radioactive rhenium. Results of our carried out studies on the main properties of the same complexes present in the solution at the nanogram concentrations (n.c.a. scale, real radiopharmaceutical conditions) using the tricarbonyl synthon with the [188Re]-radionuclide and its congener – metastable gamma radiation emitter [99mTc]1 will be published in a separate paper.
1 The 99mTc radionuclide is considered to be one of the most popular diagnostic radioisotopes. About 80% of the analytical procedures performed in the nuclear medicine applies different [99mTc]-containing agents [8].
L. Fuks et al. / Polyhedron 29 (2010) 634–638
2. Experimental Commercially available samples of thiosalicylic acid (1a) and methyl thiosalicylate (1b) were purchased from Sigma–Aldrich. Solvents used in the syntheses of the investigated complexes and for crystallization were purchased from Polish Chemical Reagents S.A. as pure p.a. and used without further purification. Water used was doubly distilled from quartz. Pale yellow crystals of 1a suitable for X-ray diffraction studies, were obtained by crystallization from THF/methanol (3:1) solution. 2.1. Synthesis of bis(2-mercaptobenzoic acid)hexacarbonyl dirhenium(I) (2a)
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quantum chemical calculations using either the PM3 method or B3LYP/LanL2DZ method within the Density Functional Theory (DFT) framework resulted in the geometry of heavy metal complexes in good agreement with the experimental data [12,13]. Taking this into account calculations on the more advanced level have been not performed in this study. 2.4. IR spectra All spectra were recorded in solid KBr pellets in the range 4000– 800 cm1 using Bruker Equinox 55 FT-IR spectrophotometer with 50 scans each and with spectral resolution of 1 cm1. 2.5. X-ray studies
For the 2a synthesis we adopted procedure proposed by Schöster and Zeisler [10]. Thiosalicylic acid (1a) (35 mg, 0.227 mmol) was dissolved in THF (2 mL) and added to the colorless solution of Re(CO)5Cl (85.2 mg, 0.235 mmol) in 10 mL of THF. After 48 h of stirring at room temperature, under nitrogen and in darkness, clear, yellow solution was left for slow crystallization (room temperature). Yellow crystals were consecutively washed gently with water, MeOH and dried in vacuum to give the product suitable for X-ray diffraction studies. Mass spectroscopy: TOF MS ES+: m/z 790 (M-2CO+H+), calc. 846.8 g/mol (dimer, values will be discussed later). Elementary anal.: Calcd: C, 28.34; H, 1.18; S, 7.56. Found: C, 28.87; H, 1.13; S, 7.73%. 1 H NMR (CD3OD): 8.28 (d, 1H,Ar), 7.51–7.45 (q, 2H, Ar), 7.40 (t, 1H, Ar); for analytical purposes 1H NMR of 1a (CD3OD) has also been registered: 7.98 (d, 1H, Ar), 7.34 (d, 1H, Ar), 7.28 (t, 1H, Ar), 7.13 (t, 1H, Ar). The proton signals of SH and COOH groups have not been detected because of their fast exchange with deuterium from the OD group of the solvent. IR (KBr, cm1): 2017, 1923, 1890. 2.2. Synthesis of methyl thiosalicylate of tricarbonyl(I)rhenium complex (2b) The synthesis of tricarbonylrhenium(I) complex with bidentate methyl thiosalicylate ligand was performed according to the procedure described in ref. [9]. (NEt4)2[ReBr3(CO)3] (101 mg; 0.13 mmol) was dissolved in 10 ml of water. After addition of 70 mg (0.40 mmol) of aqueous solution of AgNO3 the reaction mixture was stirred at room temperature for 3 h (under nitrogen, in darkness) and centrifuged. Solid AgBr precipitate was removed and 21.87 mg of 1b (0.13 mmol) was added to the colorless supernatant liquid. The reaction mixture was stirred for 2 h at 50 °C and the final product precipitated as a yellow powder. It was filtered off, washed with water and THF, and dried in vacuum. Elementary anal: Calcd: C, 29.01; H, 1.99; S, 7.04. Found: C, 28.85; H, 1.93; S, 7.06%. 1 H NMR: (CD3SOCD3): 8.04 (d, 1H, Ar), 7.48–7.45 (q, 2H, Ar), 7.25 (t, 1H, Ar), 4.09–4.01 (2H, H2O), 3.89 (s, 3H, CH3); as previously, 1H NMR registered for 1b (CD3SOCD3): 7.90 (d, 1H, Ar), 7.56 (d, 1H, Ar), 7.41 (t, 1H, Ar), 7.21 (t, 1H, Ar), 5.31 (s, 1H, SH), 3.83 (s, 3H, CH3). IR (KBr, cm1): 2017, 1923, 1890. All rhenium complexes investigated in this study are presented in Fig. 1. 2.3. Calculations Calculations were carried out by using the SPARTAN 2008 program [11] running on the PC. Semiempirical geometry optimization was performed at the PM3 level. It has already been demonstrated that
X-ray crystallographic data for 1a and 2a were collected on the KUMA KM4 four-circle diffractometer operating in the x–2h mode. Structures were solved by direct method [14] and refined by the full-matrix least-squares method [15]. The reflections were processed using profile analysis and corrected for the Lorentz factor and polarization effect. The heavy atom i.e. Re was located by applying Patterson’s method and the positions of other non-hydrogen atoms were determined in the course of successive refinement using the SHELXLS program. Final refinement on F2 by the full-matrix least squares method was performed on positional parameters of all atoms, anisotropic temperature factors of all non H-atoms and isotropic temperature factors of hydrogen atoms. Weighting scheme was used in the following form: w = 1/[r2(F2o) + (A P)2 + B P], where P = [Max(F2o,0)+2Fc2]/3. Calculations were carried out using the SHELXL97 program [14,15]. A summary of the experimental details is presented in Table 1. 3. Results and discussion Positions of the most important IR bands of the two studied ligands (1a and 1b) and their ReI complexes (2a and 2b) are listed in Table 2 together with their proposed assignment. All main bands in the fingerprint region of the ligands appear also in the IR spectra of the complexes. Also the three characteristic peaks of the Re–(CO) vibrations (namely 2017, 1923, 1890 cm1 for 2a and 2035, 1974, 1892 cm1 for 2b), which appear in the spectra of both complexes, confirm the existence of the tricarbonylrhenium core. According to the existing literature (e.g. [16,17]) the presence of multiple peaks registered in the region of 2000 cm1 is a proof for the cis arrangement of the carbonyl groups. Appearance of three peaks suggests the decrease of the ideal c4v symmetry, caused, among other factors, by inequality of the two planar CO groups. It seems to be important to pay special attention to stretching vibrations of the carboxylic –C@O bond (1600 cm1). Significant shift from 1713 cm1 registered for free 1b to 1627 cm1 for 2b (equal to 86 cm1) is almost twice as large as that for the 1a–2a pair (namely, 53 cm1). At the present stage of our knowledge we may postulate that while in the course of 2b complex formation the ReI cation accepts electrons from the –C@O oxygen atom, in the 2a complex the electrons are supplied by uniform carboxylic group. Molecular structures of the 1a and 2a determined in this work, together with atom labelling, are shown in Fig. 2. They seem to agree well with conclusions already presented in Refs. [18,17], respectively. Selected bond lengths and bond angles (experimental and calculated values) are listed in Table 3. The data obtained for 2a species confirm the schematic structure of this compound proposed by Hieber and Röhm from the analysis of indirect experimental methods, e.g. the IR spectra and elementary analysis [17].
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Fig. 1. Rhenium complexes investigated in the presented paper.
Table 1 Summary of the structure refinement parameters for 1a and 2a.
Empirical formula Cell weight Z T (K) k (Å) Crystal system Space group Unit cell dimensions a (Å) b (Å) c (Å) a (°) b (°) c (°) V (Å3) Dcalc (g cm3) l (Mo Ka) (mm1) F(0 0 0) Crystal size (mm) Maximum 2h for data collection (°) Index range Numbered of measured reflections Numbered of unique reflections with Fo > 4r(Fo) Rint Method of structure solution Method of structure refinement Number of parameters refined Goodness-of-fit (GOF) on F2
1a
2a
C7H6O2S 616.71 4 293(2) 0.71073 monoclinic P21/c
(C20H10O10S2Re2)22THF 1982.02 2 293(2) 0.71073 triclinic P1
7.8667(16) 5.9636(12) 14.954(3) 90.00 (3) 100.50(3) 90.00 689.802 1.485 0.40 320 0.36 0.15 0.05 54.14 10 6 h 6 0, 0 6 k 6 7, 18 6 l 6 17 1758 1492 0.0407 Patterson method full-matrix least squares on F2 69 1.045
9.2444(19) 9.6209(19) 18.2812(4) 96.099(3) 97.458(3) 93.711(3) 1597.95(6) 2.060 7.76 944 0.62 0.35 0.29 54.88 11 6 h 6 12, 12 6 k 6 0, 22 6 l 6 22 7063 6665 0.0701 Patterson method full-matrix least squares on F2 307 1.121
For 1a our data agree within the experimental error with those obtained by Steiner [18] and by Aggarwal and Biswas [19]. The aim of our X-ray crystallographic studies of thiosalicylic acid was to characterize and compare the structure of the ligand with that of the corresponding complex, both obtained under the same conditions (e.g. crystallized from the same solvent).
Comparison of the experimental structural data for 1a with those obtained from calculations shows that for main bond lengths and angles the mean differences between the two types of data are 0.017 Å and 2°, respectively. Such small differences strongly suggest that calculated structural data for 1b molecule (Table 3), which is similar to 1a (both do not contain heavy atoms), should
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L. Fuks et al. / Polyhedron 29 (2010) 634–638 Table 2 Main IR bands (cm1) of the compounds studied together with their vibrational assignment. Band assignment
cRe(CO) cRe(CO) cRe(CO) cC@O cOH2 cSH cCH3 ;sym cCH3 ;asym cOH a
Table 3 Selected bond lengths (Å) and angles (°) in the studied compounds (experimental and calculated data); for numbering of atoms see Figs. 1 and 2.
Band position (cm1)
1a a
1a
2a
1675
2017 1923 1890 1622
2523
1b
1713
2b
Exp.
2035 1974 1892 1627 3418
2553 2953
2954
3025
2927
Bond lengths Re1–O4 Re1–S1 Re1–S10 Re1–O6 Re1–C2 Re1–C1 Re1–C3 C10@O4 C5–S1 C10–O5 |Mean differ.|
3050–2835
Dimer (see discussion below).
be very close to real values. Because 1b is an oily compound, method of the X-ray diffraction on the monocrystals could not be applied. From the crystallographic data obtained for the dinuclear 2a complex (shown in Table 3 and Fig. 2) we can conclude that each ReI cation is octahedrally coordinated by three CO groups and three electron donor atoms (namely, O, S, S) from two 1a ligand molecules. The two CO molecules present in the equatorial plane form together with ReI the 90.9° angle, which means that no additional interactions between the carbonyl groups appear upon complex formation. On the other hand, the experimentally found O4– Re1–S1 bond angle is only 81.4° (the analogous N–Re–O bond angle found for the ReI-pyridine carboxyamide is even smaller, being equal to about 74° [13]). Such deviation from the ideal value of 90° can be explained by the relatively strong tensions appearing in the six-membered ring formed by the bidentately chelating ligand and the ReI cation. It can be also seen that both C–Re1–S axial angles are about 174°. The three Re–C bond distances (with mean value of about 1.9 Å) are in the range shown by numerous other ReI complexes containing the Re(CO)3+ core [16]. The Re1–O4, Re1–S1 and Re1–S10 bond distances are 2.16, 2.46 and 2.52 Å, respectively. The Re1–S1 and Re1–S10 distances in the 2a dimer do not differ significantly from the two Re–S distances in the Re2(CO)6(L)2 dimers determined by e.g. Czerwieniec et al. [20], Carballo et al. [21], or Benkstein et al. [22]. Therefore, it can be concluded that in the dimeric 2a complex the geometry around each ReI center is slightly distorted octahedral. However, we can expect that ReI complexed by 1a at nanomolar concentrations (conditions of the synthesis
Angles C3–Re1–O6 C2–Re1–S1 C1–Re1–C2 O4–Re1–S1 C4–C5–S1 C4–C10–O4 O4–C10–O5 |Mean differ.| a
1.220 1.771 1.315 0.017
121.62 114.24 122.01 1.97
2aa Exp.
3aa Calc.
2.163 2.461 2.523
2.174 2.413
2.208 2.582
2.459 1.913 1.875 1.880 1.220 1.784 1.329
2.524 1.897 1.890 1.871 1.250 1.819 1.345
1b Calc.
2b Calc.
Calc.
1.221 1.753 1.349
124.75 127.10 109.36
1.930 1.860 1.934 1.181 1.790 1.316 0.025
171.50 90.87 83.17 124.48 127.78 122.14 5.48
1.223 1.766 1.363
168.90
177.71
89.49 81.42 123.64 109.87 116.61
90.46 82.75 127.95 126.01 105.21
126.10 121.56 103.36
Dimer (2a)/monomer (3a) (see discussion below).
of radiopharmaceuticals, the so-called n.c.a. scale) does not exist in the dimeric form. This problem will be discussed in a separate paper describing the nanoscale properties of the tricarbonyl 99mTcI and 188ReI complexes. From the existing literature data it can be concluded that in the monomeric 3a species (see Fig. 3) the axial position in the distorted octahedron with ReI in its center is occupied by water molecule and the species is negatively charged. Structural data for this complex obtained from the QM calculations (presented in Table 3) are in a reasonably good agreement with those obtained experimentally for the dimeric complex 2a (mean difference in the bond lengths is about 0.02 Å and in bond angles about 5.5°). Numerous attempts to obtain crystals of 2b, suitable for the Xray diffraction studies have failed. Hence, quantum chemical calculations (results are presented in Table 3) and the registered IR spectra (see, Table 2) are the main source of structural information on this complex. Disappearance of the S–H valence vibrations (ca. 2550 cm1) in the IR spectrum of 2b combined with relatively
Fig. 2. ORTEP plot of 1a and 2a. Ellipsoids are drawn at the 50% probability level.
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L. Fuks et al. / Polyhedron 29 (2010) 634–638
Fig. 3. Schematic presentation of the 3a (left) and 2b (right) based on the QM calculations.
great shift of the peak assigned to the –C@O vibrations upon complex formation (Dm 86 cm1) suggest coordination of the Re(CO)3+ cation by S1 and O4 of the 1b ligand. The remaining coordination site of the cation is occupied by the water molecule. This has been proved by the elementary analysis and by the 1H NMR and IR spectra. The proposed structure of the 2b complex is schematically shown in Fig. 3. Supplementary data CCDC 730210 contains the supplementary crystallographic data for 2a. These data can be obtained free of charge via http:// www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: [email protected]. Acknowledgements We thank Dr. Wojciech Starosta (Institute of Nuclear Chemistry and Technology, Warsaw, Poland) for performing the X-ray studies. References [1] V.J. Lewington, J. Nucl. Med. 46 (2005) 38S. [2] J. Blachot et al., Int. J. Appl. Radiat. Isotopes 20 (1969) 467. [3] Nuclides 2000, An Electronic Chart of the Nuclides, Version 1.00, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, 1999.
[4] W. Leppert, E. Nowakowska, Medycyna Paliatywna w Praktyce (Paliative Medicine in Practice), 2 (2008) 33 (in Polish). [5] S.X. Wang, A. Bao, S.J. Herrera, W.T. Phillips, B. Goins, C. Santoyo, F.R. Miller, R.A. Otto, Clin. Cancer Res. 14 (2008) 3975. [6] R. Alberto, R. Schibli, A. Egli, P.A. Schubiger, W.A. Herrmann, U. Abram, Th.A. Kaden, J. Organomet. Chem. 493 (1995) 119. [7] R. Schibli, R. Bella, R. Alberto, E. Garcia-Garayoa, K. Ortner, U. Abram, P.A. Schubiger, Bioconjugate Chem. 11 (2000) 345. and refs. cited therein. [8] Development of 99mTc agents for imaging central neural system receptors, IAEA Technical Report TRS46, Vienna, 2004. [9] S. Mundwiler, M. Kundig, K. Ortner, R. Alberto, Dalton Trans. 9 (2004) 1320. [10] F.S. Schöster, S.K. Zeisler, J. Radioanal, Nucl. Chem. 220 (1997) 149. [11] SPARTAN’08, Wavefunction Inc., Irvine CA, USA, 2006–2009. ISBN978-1-89066138-4. [12] L. Fuks, N. Sadlej-Sosnowska, K. Samochocka, W. Starosta, J. Mol. Struct. 740 (2005) 229. [13] L. Fuks, E. Gniazdowska, J. Mieczkowski, N. Sadlej-Sosnowska, Polyhedron 27 (2008) 1353. [14] G.M. Sheldrick, Acta Crystallogr. A46 (1990) 467. [15] G.M. Sheldrick, SHELXL97, Program for Refinement of Crystal Structure, University of Göttingen, Göttingen, 1997. [16] K. Schwochau, Technetium Chemistry and Radiopharmaceutical Applications, Wiley-VCH, 2000, p. 328. [17] W. Hieber, W. Röhm, Chem. Ber. 102 (1969) 2787. [18] T. Steiner, Acta Crystallogr. C36 (2000) 876. [19] Aggarwal, Biswas, Indian J. Pure Appl. Phys. 2 (1964) 269. [20] R. Czerwieniec, A. Kapturkiewicz, J. Nowacki, Inorg. Chem. Commun. 8 (2005) 34. [21] R. Carballo, J.S. Casas, E. Garcia-Martinez, G. Pereiras-Gabian, A. Sanchez, J. Sordo, E.M. Vazquez-Lopez, J.C. Garcia-Monteagudo, U. Abram, J. Organomet. Chem. 656 (2002) 1. [22] K.D. Benkstein, J.T. Hupp, C.L. Stern, Inorg. Chem. 37 (1998) 5404.
Contents lists available at ScienceDirect
Polyhedron journal homepage: www.elsevier.com/locate/poly
Tricarbonylrhenium(I) complexes with anionic ligands containing S and O donor atoms – potential radiopharmaceutical precursors Leon Fuks, Ewa Gniazdowska, Przemysław Koz´min´ski * Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland
a r t i c l e
i n f o
Article history: Available online 9 September 2009 Keywords: Tricarbonylrhenium(I) Thiosalicylic derivatives Molecular structure X-ray diffraction IR spectra Quantum chemical calculations
a b s t r a c t Equilibrium geometry of tricarbonylrhenium(I) thiosalicylate and of methylthiosalicylate has been determined by the X-ray diffraction studies as well as calculated by the semiempirical method using the PM3 functional basis set. Infrared spectra of the species have also been studied in the 4000800 cm1 range of wavenumbers. The experimental and theoretical data are in satisfactory agreement. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Radionuclides are used in numerous medicinal diagnostic and/ or therapeutic procedures. Such techniques have increased the demand for new complexes containing carrier-free radionuclides having reasonable half lives and proper energy of radiation. Rhenium-188 (Re-188), a decay product of tungsten-188 (W-188), is one of the promising therapeutic radionuclides. This radionuclide has favorable nuclear properties: half-life time of 16.98 h, beta radiation of 2.12 MeV accompanied by gamma radiation (Ec = 155 keV, 15% of total emitted energy), which make it ideal for imaging of tumors using gamma cameras [1]. Because the radionuclide is available in nuclear medicine clinics at a reasonably low price from the W-188/Re-188 generator [2] it is ideal for radiotherapeutic applications. For instance, after labelling the monoclonal antibodies with Re-188 the obtained compounds are used for targeting tumor cells. Another radionuclide of rhenium produced in nuclear reactors, the Re-186 nuclide (t1/2 = 89.3 h, Eb = 1.07 MeV, 8% of gamma emission with Ec = 137 keV [3]), should be mentioned as one among only three radionuclides approved for treatment of pain [4]. The same radionuclide, when carried by liposomes into the tumor intraoperative remnants of head and neck squamous cell carcinoma, may play a role in the management of positive surgical margins with minimal side-effects [5]. In 1995 Schubiger et al. have presented for the first time one-step synthesis of the fac-Re(CO)3(OH2)3+ complex by direct reduction of ReO4 in aqueous solution with sodium borohydride * Corresponding author. Tel.: +48 22 504 1011. E-mail addresses: [email protected], (P. Koz´min´ski).
[email protected]
0277-5387/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.poly.2009.08.030
in the presence of carbon monoxide [6]. At present, tricarbonylrhenium(I) complexes (of the octahedral or tetragonal bipyramide structure) seem to be candidates for design of new radiopharmaceuticals. Water-soluble radiopharmaceutical precursor, Re(CO)3(OH2)3+, is stable in aqueous solutions over the broad pH range (pH 2–12) for several hours. Three water molecules coordinated to the highly inert fac-Re(CO)3+ core can be easily replaced by various functional groups, such as amines, thioethers, thiols and phosphines. This can be done by using one tridentate ligand (the so-called ‘‘3+0” approach [6]) or one bidentate and one monodentate ligand (‘‘2+1” mixed-ligand complexes [7–9]). Because of small size and small charge of the fac-Re(CO)3+ group, it does not influence significantly biological properties of even the smallest biomolecules used in the synthesis of radiopharmaceuticals. This work comprises the synthesis, chemical, spectroscopic and quantum calculation (QC) studies on the tricarbonylrhenium(I) species complexed either by thiosalicylic acid (2-mercaptobenzoic acid, 2-sulfanylbenzoic acid) or by methyl thiosalicylate (methyl 2-mercaptobenzoate). All experiments were performed on the milligram scale using the non-radioactive rhenium. Results of our carried out studies on the main properties of the same complexes present in the solution at the nanogram concentrations (n.c.a. scale, real radiopharmaceutical conditions) using the tricarbonyl synthon with the [188Re]-radionuclide and its congener – metastable gamma radiation emitter [99mTc]1 will be published in a separate paper.
1 The 99mTc radionuclide is considered to be one of the most popular diagnostic radioisotopes. About 80% of the analytical procedures performed in the nuclear medicine applies different [99mTc]-containing agents [8].
L. Fuks et al. / Polyhedron 29 (2010) 634–638
2. Experimental Commercially available samples of thiosalicylic acid (1a) and methyl thiosalicylate (1b) were purchased from Sigma–Aldrich. Solvents used in the syntheses of the investigated complexes and for crystallization were purchased from Polish Chemical Reagents S.A. as pure p.a. and used without further purification. Water used was doubly distilled from quartz. Pale yellow crystals of 1a suitable for X-ray diffraction studies, were obtained by crystallization from THF/methanol (3:1) solution. 2.1. Synthesis of bis(2-mercaptobenzoic acid)hexacarbonyl dirhenium(I) (2a)
635
quantum chemical calculations using either the PM3 method or B3LYP/LanL2DZ method within the Density Functional Theory (DFT) framework resulted in the geometry of heavy metal complexes in good agreement with the experimental data [12,13]. Taking this into account calculations on the more advanced level have been not performed in this study. 2.4. IR spectra All spectra were recorded in solid KBr pellets in the range 4000– 800 cm1 using Bruker Equinox 55 FT-IR spectrophotometer with 50 scans each and with spectral resolution of 1 cm1. 2.5. X-ray studies
For the 2a synthesis we adopted procedure proposed by Schöster and Zeisler [10]. Thiosalicylic acid (1a) (35 mg, 0.227 mmol) was dissolved in THF (2 mL) and added to the colorless solution of Re(CO)5Cl (85.2 mg, 0.235 mmol) in 10 mL of THF. After 48 h of stirring at room temperature, under nitrogen and in darkness, clear, yellow solution was left for slow crystallization (room temperature). Yellow crystals were consecutively washed gently with water, MeOH and dried in vacuum to give the product suitable for X-ray diffraction studies. Mass spectroscopy: TOF MS ES+: m/z 790 (M-2CO+H+), calc. 846.8 g/mol (dimer, values will be discussed later). Elementary anal.: Calcd: C, 28.34; H, 1.18; S, 7.56. Found: C, 28.87; H, 1.13; S, 7.73%. 1 H NMR (CD3OD): 8.28 (d, 1H,Ar), 7.51–7.45 (q, 2H, Ar), 7.40 (t, 1H, Ar); for analytical purposes 1H NMR of 1a (CD3OD) has also been registered: 7.98 (d, 1H, Ar), 7.34 (d, 1H, Ar), 7.28 (t, 1H, Ar), 7.13 (t, 1H, Ar). The proton signals of SH and COOH groups have not been detected because of their fast exchange with deuterium from the OD group of the solvent. IR (KBr, cm1): 2017, 1923, 1890. 2.2. Synthesis of methyl thiosalicylate of tricarbonyl(I)rhenium complex (2b) The synthesis of tricarbonylrhenium(I) complex with bidentate methyl thiosalicylate ligand was performed according to the procedure described in ref. [9]. (NEt4)2[ReBr3(CO)3] (101 mg; 0.13 mmol) was dissolved in 10 ml of water. After addition of 70 mg (0.40 mmol) of aqueous solution of AgNO3 the reaction mixture was stirred at room temperature for 3 h (under nitrogen, in darkness) and centrifuged. Solid AgBr precipitate was removed and 21.87 mg of 1b (0.13 mmol) was added to the colorless supernatant liquid. The reaction mixture was stirred for 2 h at 50 °C and the final product precipitated as a yellow powder. It was filtered off, washed with water and THF, and dried in vacuum. Elementary anal: Calcd: C, 29.01; H, 1.99; S, 7.04. Found: C, 28.85; H, 1.93; S, 7.06%. 1 H NMR: (CD3SOCD3): 8.04 (d, 1H, Ar), 7.48–7.45 (q, 2H, Ar), 7.25 (t, 1H, Ar), 4.09–4.01 (2H, H2O), 3.89 (s, 3H, CH3); as previously, 1H NMR registered for 1b (CD3SOCD3): 7.90 (d, 1H, Ar), 7.56 (d, 1H, Ar), 7.41 (t, 1H, Ar), 7.21 (t, 1H, Ar), 5.31 (s, 1H, SH), 3.83 (s, 3H, CH3). IR (KBr, cm1): 2017, 1923, 1890. All rhenium complexes investigated in this study are presented in Fig. 1. 2.3. Calculations Calculations were carried out by using the SPARTAN 2008 program [11] running on the PC. Semiempirical geometry optimization was performed at the PM3 level. It has already been demonstrated that
X-ray crystallographic data for 1a and 2a were collected on the KUMA KM4 four-circle diffractometer operating in the x–2h mode. Structures were solved by direct method [14] and refined by the full-matrix least-squares method [15]. The reflections were processed using profile analysis and corrected for the Lorentz factor and polarization effect. The heavy atom i.e. Re was located by applying Patterson’s method and the positions of other non-hydrogen atoms were determined in the course of successive refinement using the SHELXLS program. Final refinement on F2 by the full-matrix least squares method was performed on positional parameters of all atoms, anisotropic temperature factors of all non H-atoms and isotropic temperature factors of hydrogen atoms. Weighting scheme was used in the following form: w = 1/[r2(F2o) + (A P)2 + B P], where P = [Max(F2o,0)+2Fc2]/3. Calculations were carried out using the SHELXL97 program [14,15]. A summary of the experimental details is presented in Table 1. 3. Results and discussion Positions of the most important IR bands of the two studied ligands (1a and 1b) and their ReI complexes (2a and 2b) are listed in Table 2 together with their proposed assignment. All main bands in the fingerprint region of the ligands appear also in the IR spectra of the complexes. Also the three characteristic peaks of the Re–(CO) vibrations (namely 2017, 1923, 1890 cm1 for 2a and 2035, 1974, 1892 cm1 for 2b), which appear in the spectra of both complexes, confirm the existence of the tricarbonylrhenium core. According to the existing literature (e.g. [16,17]) the presence of multiple peaks registered in the region of 2000 cm1 is a proof for the cis arrangement of the carbonyl groups. Appearance of three peaks suggests the decrease of the ideal c4v symmetry, caused, among other factors, by inequality of the two planar CO groups. It seems to be important to pay special attention to stretching vibrations of the carboxylic –C@O bond (1600 cm1). Significant shift from 1713 cm1 registered for free 1b to 1627 cm1 for 2b (equal to 86 cm1) is almost twice as large as that for the 1a–2a pair (namely, 53 cm1). At the present stage of our knowledge we may postulate that while in the course of 2b complex formation the ReI cation accepts electrons from the –C@O oxygen atom, in the 2a complex the electrons are supplied by uniform carboxylic group. Molecular structures of the 1a and 2a determined in this work, together with atom labelling, are shown in Fig. 2. They seem to agree well with conclusions already presented in Refs. [18,17], respectively. Selected bond lengths and bond angles (experimental and calculated values) are listed in Table 3. The data obtained for 2a species confirm the schematic structure of this compound proposed by Hieber and Röhm from the analysis of indirect experimental methods, e.g. the IR spectra and elementary analysis [17].
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Fig. 1. Rhenium complexes investigated in the presented paper.
Table 1 Summary of the structure refinement parameters for 1a and 2a.
Empirical formula Cell weight Z T (K) k (Å) Crystal system Space group Unit cell dimensions a (Å) b (Å) c (Å) a (°) b (°) c (°) V (Å3) Dcalc (g cm3) l (Mo Ka) (mm1) F(0 0 0) Crystal size (mm) Maximum 2h for data collection (°) Index range Numbered of measured reflections Numbered of unique reflections with Fo > 4r(Fo) Rint Method of structure solution Method of structure refinement Number of parameters refined Goodness-of-fit (GOF) on F2
1a
2a
C7H6O2S 616.71 4 293(2) 0.71073 monoclinic P21/c
(C20H10O10S2Re2)22THF 1982.02 2 293(2) 0.71073 triclinic P1
7.8667(16) 5.9636(12) 14.954(3) 90.00 (3) 100.50(3) 90.00 689.802 1.485 0.40 320 0.36 0.15 0.05 54.14 10 6 h 6 0, 0 6 k 6 7, 18 6 l 6 17 1758 1492 0.0407 Patterson method full-matrix least squares on F2 69 1.045
9.2444(19) 9.6209(19) 18.2812(4) 96.099(3) 97.458(3) 93.711(3) 1597.95(6) 2.060 7.76 944 0.62 0.35 0.29 54.88 11 6 h 6 12, 12 6 k 6 0, 22 6 l 6 22 7063 6665 0.0701 Patterson method full-matrix least squares on F2 307 1.121
For 1a our data agree within the experimental error with those obtained by Steiner [18] and by Aggarwal and Biswas [19]. The aim of our X-ray crystallographic studies of thiosalicylic acid was to characterize and compare the structure of the ligand with that of the corresponding complex, both obtained under the same conditions (e.g. crystallized from the same solvent).
Comparison of the experimental structural data for 1a with those obtained from calculations shows that for main bond lengths and angles the mean differences between the two types of data are 0.017 Å and 2°, respectively. Such small differences strongly suggest that calculated structural data for 1b molecule (Table 3), which is similar to 1a (both do not contain heavy atoms), should
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L. Fuks et al. / Polyhedron 29 (2010) 634–638 Table 2 Main IR bands (cm1) of the compounds studied together with their vibrational assignment. Band assignment
cRe(CO) cRe(CO) cRe(CO) cC@O cOH2 cSH cCH3 ;sym cCH3 ;asym cOH a
Table 3 Selected bond lengths (Å) and angles (°) in the studied compounds (experimental and calculated data); for numbering of atoms see Figs. 1 and 2.
Band position (cm1)
1a a
1a
2a
1675
2017 1923 1890 1622
2523
1b
1713
2b
Exp.
2035 1974 1892 1627 3418
2553 2953
2954
3025
2927
Bond lengths Re1–O4 Re1–S1 Re1–S10 Re1–O6 Re1–C2 Re1–C1 Re1–C3 C10@O4 C5–S1 C10–O5 |Mean differ.|
3050–2835
Dimer (see discussion below).
be very close to real values. Because 1b is an oily compound, method of the X-ray diffraction on the monocrystals could not be applied. From the crystallographic data obtained for the dinuclear 2a complex (shown in Table 3 and Fig. 2) we can conclude that each ReI cation is octahedrally coordinated by three CO groups and three electron donor atoms (namely, O, S, S) from two 1a ligand molecules. The two CO molecules present in the equatorial plane form together with ReI the 90.9° angle, which means that no additional interactions between the carbonyl groups appear upon complex formation. On the other hand, the experimentally found O4– Re1–S1 bond angle is only 81.4° (the analogous N–Re–O bond angle found for the ReI-pyridine carboxyamide is even smaller, being equal to about 74° [13]). Such deviation from the ideal value of 90° can be explained by the relatively strong tensions appearing in the six-membered ring formed by the bidentately chelating ligand and the ReI cation. It can be also seen that both C–Re1–S axial angles are about 174°. The three Re–C bond distances (with mean value of about 1.9 Å) are in the range shown by numerous other ReI complexes containing the Re(CO)3+ core [16]. The Re1–O4, Re1–S1 and Re1–S10 bond distances are 2.16, 2.46 and 2.52 Å, respectively. The Re1–S1 and Re1–S10 distances in the 2a dimer do not differ significantly from the two Re–S distances in the Re2(CO)6(L)2 dimers determined by e.g. Czerwieniec et al. [20], Carballo et al. [21], or Benkstein et al. [22]. Therefore, it can be concluded that in the dimeric 2a complex the geometry around each ReI center is slightly distorted octahedral. However, we can expect that ReI complexed by 1a at nanomolar concentrations (conditions of the synthesis
Angles C3–Re1–O6 C2–Re1–S1 C1–Re1–C2 O4–Re1–S1 C4–C5–S1 C4–C10–O4 O4–C10–O5 |Mean differ.| a
1.220 1.771 1.315 0.017
121.62 114.24 122.01 1.97
2aa Exp.
3aa Calc.
2.163 2.461 2.523
2.174 2.413
2.208 2.582
2.459 1.913 1.875 1.880 1.220 1.784 1.329
2.524 1.897 1.890 1.871 1.250 1.819 1.345
1b Calc.
2b Calc.
Calc.
1.221 1.753 1.349
124.75 127.10 109.36
1.930 1.860 1.934 1.181 1.790 1.316 0.025
171.50 90.87 83.17 124.48 127.78 122.14 5.48
1.223 1.766 1.363
168.90
177.71
89.49 81.42 123.64 109.87 116.61
90.46 82.75 127.95 126.01 105.21
126.10 121.56 103.36
Dimer (2a)/monomer (3a) (see discussion below).
of radiopharmaceuticals, the so-called n.c.a. scale) does not exist in the dimeric form. This problem will be discussed in a separate paper describing the nanoscale properties of the tricarbonyl 99mTcI and 188ReI complexes. From the existing literature data it can be concluded that in the monomeric 3a species (see Fig. 3) the axial position in the distorted octahedron with ReI in its center is occupied by water molecule and the species is negatively charged. Structural data for this complex obtained from the QM calculations (presented in Table 3) are in a reasonably good agreement with those obtained experimentally for the dimeric complex 2a (mean difference in the bond lengths is about 0.02 Å and in bond angles about 5.5°). Numerous attempts to obtain crystals of 2b, suitable for the Xray diffraction studies have failed. Hence, quantum chemical calculations (results are presented in Table 3) and the registered IR spectra (see, Table 2) are the main source of structural information on this complex. Disappearance of the S–H valence vibrations (ca. 2550 cm1) in the IR spectrum of 2b combined with relatively
Fig. 2. ORTEP plot of 1a and 2a. Ellipsoids are drawn at the 50% probability level.
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L. Fuks et al. / Polyhedron 29 (2010) 634–638
Fig. 3. Schematic presentation of the 3a (left) and 2b (right) based on the QM calculations.
great shift of the peak assigned to the –C@O vibrations upon complex formation (Dm 86 cm1) suggest coordination of the Re(CO)3+ cation by S1 and O4 of the 1b ligand. The remaining coordination site of the cation is occupied by the water molecule. This has been proved by the elementary analysis and by the 1H NMR and IR spectra. The proposed structure of the 2b complex is schematically shown in Fig. 3. Supplementary data CCDC 730210 contains the supplementary crystallographic data for 2a. These data can be obtained free of charge via http:// www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: [email protected]. Acknowledgements We thank Dr. Wojciech Starosta (Institute of Nuclear Chemistry and Technology, Warsaw, Poland) for performing the X-ray studies. References [1] V.J. Lewington, J. Nucl. Med. 46 (2005) 38S. [2] J. Blachot et al., Int. J. Appl. Radiat. Isotopes 20 (1969) 467. [3] Nuclides 2000, An Electronic Chart of the Nuclides, Version 1.00, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, 1999.
[4] W. Leppert, E. Nowakowska, Medycyna Paliatywna w Praktyce (Paliative Medicine in Practice), 2 (2008) 33 (in Polish). [5] S.X. Wang, A. Bao, S.J. Herrera, W.T. Phillips, B. Goins, C. Santoyo, F.R. Miller, R.A. Otto, Clin. Cancer Res. 14 (2008) 3975. [6] R. Alberto, R. Schibli, A. Egli, P.A. Schubiger, W.A. Herrmann, U. Abram, Th.A. Kaden, J. Organomet. Chem. 493 (1995) 119. [7] R. Schibli, R. Bella, R. Alberto, E. Garcia-Garayoa, K. Ortner, U. Abram, P.A. Schubiger, Bioconjugate Chem. 11 (2000) 345. and refs. cited therein. [8] Development of 99mTc agents for imaging central neural system receptors, IAEA Technical Report TRS46, Vienna, 2004. [9] S. Mundwiler, M. Kundig, K. Ortner, R. Alberto, Dalton Trans. 9 (2004) 1320. [10] F.S. Schöster, S.K. Zeisler, J. Radioanal, Nucl. Chem. 220 (1997) 149. [11] SPARTAN’08, Wavefunction Inc., Irvine CA, USA, 2006–2009. ISBN978-1-89066138-4. [12] L. Fuks, N. Sadlej-Sosnowska, K. Samochocka, W. Starosta, J. Mol. Struct. 740 (2005) 229. [13] L. Fuks, E. Gniazdowska, J. Mieczkowski, N. Sadlej-Sosnowska, Polyhedron 27 (2008) 1353. [14] G.M. Sheldrick, Acta Crystallogr. A46 (1990) 467. [15] G.M. Sheldrick, SHELXL97, Program for Refinement of Crystal Structure, University of Göttingen, Göttingen, 1997. [16] K. Schwochau, Technetium Chemistry and Radiopharmaceutical Applications, Wiley-VCH, 2000, p. 328. [17] W. Hieber, W. Röhm, Chem. Ber. 102 (1969) 2787. [18] T. Steiner, Acta Crystallogr. C36 (2000) 876. [19] Aggarwal, Biswas, Indian J. Pure Appl. Phys. 2 (1964) 269. [20] R. Czerwieniec, A. Kapturkiewicz, J. Nowacki, Inorg. Chem. Commun. 8 (2005) 34. [21] R. Carballo, J.S. Casas, E. Garcia-Martinez, G. Pereiras-Gabian, A. Sanchez, J. Sordo, E.M. Vazquez-Lopez, J.C. Garcia-Monteagudo, U. Abram, J. Organomet. Chem. 656 (2002) 1. [22] K.D. Benkstein, J.T. Hupp, C.L. Stern, Inorg. Chem. 37 (1998) 5404.