Syn-Anti Isomerism in a Mixed-Ligand Oxorhenium Complex, ReO[SN(R)S][S]

Article abstract of DOI:10.1021/ic9604167

The simultaneous action of the tridentate ligand (C₂H₅)₂NCH₂CH₂N(CH ₂CH₂SH)₂ and the monodentate coligand HSC₆H₄OCH₃ on a suitable ReO³⁺ precursor results in a mixture of syn- and anti-oxorhenium complexes, ReO[(C₂H₅)₂NCH₂CH ₂N(CH₂CH₂S)₂] [SC₆H₄OCH₃], in a ratio of 25/1. The complexes are prepared by a ligand exchange reaction using ReO(eg)₂ (eg = ethylene glycol), ReOCl₃(PPh₃)₂, or Re(V)-citrate as precursor. Both complexes have been characterized by elemental analysis, FT-IR, UV-vis, X-ray crystallography, and NMR spectroscopy. The syn isomer C₁₇H₂₉N₂O₂S₃Re crystallizes in the monoclinic space group P2₁ln, a = 14.109(4) ?, b = 7.518(2) ?, c = 20.900(5) ?, β= 103.07(1)°, V = 2159.4(9) ?³, Z = 4. The anti isomer C₁₇H₂₉N₂O₂S₃-Re crystallizes in P2₁In, a = 9.3850(7) ?, b = 27.979(2) ?, c = 8.3648(6) ?, β= 99.86(1)°, V= 2163.9(3) ?³, Z = 4. Complete NMR studies show that the orientation of the N substituent chain with respect to the Re=O core greatly influences the observed chemical shifts. Complexes were also prepared at the tracer (¹⁸⁶Re) level by using ¹⁸⁶Re-citrate as precursor. Corroboration of the structure at tracer level was achieved by comparative HPLC studies.

Full text of DOI:10.1021/ic9604167

Inorg. Chem. 1996, 35, 7377-7383
7377
Syn-Anti Isomerism in a Mixed-Ligand Oxorhenium Complex, ReO[SN(R)S][S]
M. S. Papadopoulos, I. C. Pirmettis, M. Pelecanou, C. P. Raptopoulou, A. Terzis,
C. I. Stassinopoulou, and E. Chiotellis*
Institutes of Radioisotopes-Radiodiagnostic Products, Biology, and Materials Science,
NCSR “Demokritos”, POB 60228, 15310, Aghia Paraskevi, Athens, Greece
ReceiVed April 17, 1996X
The simultaneous action of the tridentate ligand (C2H5)2NCH2CH2N(CH2CH2SH)2 and the monodentate coligand
HSC6H4OCH3 on a suitable ReO3+ precursor results in a mixture of syn- and anti-oxorhenium complexes, ReO-
[(C2H5)2NCH2CH2N(CH2CH2S)2] [SC6H4OCH3], in a ratio of 25/1. The complexes are prepared by a ligand
exchange reaction using ReO(eg)2 (eg ) ethylene glycol), ReOCl3(PPh3)2, or Re(V)-citrate as precursor. Both
complexes have been characterized by elemental analysis, FT-IR, UV-vis, X-ray crystallography, and NMR
spectroscopy. The syn isomer C17H29N2O2S3Re crystallizes in the monoclinic space group P21/n, a ) 14.109(4)
Å, b ) 7.518(2) Å, c ) 20.900(5) Å, â ) 103.07(1)°, V ) 2159.4(9) Å3, Z ) 4. The anti isomer C17H29N2O2S3-
Re crystallizes in P21/n, a ) 9.3850(7) Å, b ) 27.979(2) Å, c ) 8.3648(6) Å, â ) 99.86(1)°, V ) 2163.9(3) Å3,
Z ) 4. Complete NMR studies show that the orientation of the N substituent chain with respect to the RedO
core greatly influences the observed chemical shifts. Complexes were also prepared at the tracer (186Re) level by
using 186Re-citrate as precursor. Corroboration of the structure at tracer level was achieved by comparative HPLC
studies.
Introduction
equimolar quantities of the tridentate and monodentate coligands
on a suitable TcO3+ precursor.3 This ligand system has been
shown to form complexes of the same structure at the tracer
level (99mTc). Distribution studies in mice demonstrated
significant uptake and retention of these 99mTc complexes in
the brain.4
The coordination chemistry of technetium and rhenium
currently is attracting much attention due to the radionuclide-
based application in radiopharmaceuticals. 99mTc is the radio-
nuclide of choice for diagnostic imaging due to its ideal nuclear
properties (t1/2 ) 6 h, γ ) 140 keV) and wide availability. On
the other hand, 186Re and 188Re as â-emitters (Emax ) 1.1 and
2.1 MeV, respectively) are two of the most promising candidates
for radiotherapy.1 The half-life of 186Re is 90.64 h with a γ-line
of 137 keV (9.5%), and the half-life of 188Re is 17 h with a
γ-line of 155 keV (15%).
Our recent work involves the study of mixed-ligand systems
(3+1 combination) as chelating systems for oxotechnetium. We
have reported previously the synthesis and characterization of
a series of neutral, lipophilic technetium complexes, TcOL1L2,
where L1H2 is a tridentate ligand (SNS donor atom set) and
L2H is a monodentate thiol acting as coligand.2 Formation of
these complexes is based on the simultaneous action of
Rhenium, as technetium’s third-row congener, exhibits many
of the chemical properties of technetium.5 Because of the
analogy in the chemistry of rhenium and technetium and the
recent availability of radionuclides of rhenium, the use of this
ligand combination [3+1, (SNS)(S) donor atom set] may be
further expanded for the preparation of rhenium complexes for
therapeutic applications. We report here the synthesis, structure,
and chemical properties of a representative complex of the
general formula ReOL1L2, where L1H2 ) (C2H5)2NCH2-
CH2N(CH2CH2SH)2 and L2H ) HSC6H4OCH3. Since upon
complexation the N substituent of the tridentate ligand can
assume the syn or anti configuration with respect to the ReO3+
core, two diastereomeric complexes theoretically are possible.6
Indeed, we have successfully isolated the two isomers: syn
(complex 1) with the side chain on nitrogen directed toward
the RedO core and anti (complex 2) with the side chain directed
away from the RedO core (Chart 1). Both complexes were
characterized by elemental analysis and spectroscopic methods.
* Address correspondence to Efstratios Chiotellis, Ph.D., Institute of
Radioisotopes-Radiodiagnostic Products, 15310 Ag. Paraskevi, Athens,
Greece. Telephone +301 6513793. Fax: +301 6543526.
X Abstract published in AdVance ACS Abstracts, October 1, 1996.
(1) (a) Volkert, W.; Ketring, A. J. Nucl. Med. 1991, 32, 174. (b) Deutsch,
E.; Libson, K.; Vanderheyden, J.-L.; Ketring, A. R.; Maxin, H.R. J.
Nucl. Med. Biol. 1986, 13, 465. (c) Fritzeberg, A. R.; Vanderheyden,
J.-L.; Rao, T. N.; Kasina, S.; Eshima, D.; Taylor, A. T. J. Nucl. Med.
1989, 30, 60. (d) DiZio, J. P.; Fiaschi, R.; Davison, A.; Jones, A. G.;
Katzenellenbogen, J. A. Bioconjugate Chem. 1991, 2, 353.
(3) (a) Pietzsch, H.-J.; Spies, H.; Hoffmann, S.; Stach, J. Lipophilic
technetium complexes-V. Inorg. Chim. Acta 1989, 161, 15. (b) Pietzch,
H.-J.; Spies, H.; Hoffmann, S.; Scheller, D. Appl. Radiat. Isotop. 1990,
41, 185. (c) Spies, H.; Johannsen, B.; Pietzsch, H.; Noll, B.; Noll, St.;
Scheunemann, M.; Fietz, T.; Berger, R.; Brust, P.; Leibnitz, P. XI
International Symposium on Radiopharmaceutical Chemistry, Van-
couver, 1995, 319 (d) Spies, H.; Fietz, T.; Glaser, M.; Pietzsch, H.;
Johannsen, B. in Technetium and Rhenium in Chemistry and Nuclear
Medicine 4; Nicolini, M., Bandoli, G., Mazzi, U., Eds.; SGE: Padova,
1995; p 243.
(4) (a) Pirmettis, I.; Papadopoulos, M.; Paschali, E.; Varvarigou, A.;
Chiotellis, E. Eur. J. Nucl. Med. 1994, 21, S7. (b) Pirmettis, I.;
Papadopoulos, M.; Mastrostamatis, S.; Tsoukalas, Ch.; Chiotellis, E.
J. Nucl. Med. 1995, 36, 145P. (c) Pirmettis, I.; Papadopoulos, M.;
Paschali, E.; Varvarigou, A. D.; Chiotellis, E. J. Nucl. Med. 1995,
36, 145P.
(2) (a) Mastrostamatis, S. G.; Papadopoulos, M. S.; Pirmettis, I. C.;
Paschali, E.; Varvarigou, A. D.; Stassinopoulou C. I.; Raptopoulou
C. P.; Terzis, A.; Chiotellis, E. J. Med. Chem. 1994, 37, 3212. (b)
Stassinopoulou, C. I.; Pelecanou, M.; Mastrostamatis, S.; Chiotellis,
E. Magn. Reson. Chem. 1994, 32, 532. (c) Spyriounis, D.; Pelecanou,
M.; Stassinopoulou, C. I.; Raptopoulou, C. P.; Terzis, A.; Chiotellis,
E. Inorg. Chem. 1995, 34, 1077. (d) Mastrostamatis, S.; Pirmettis, I.,
Papadopoulos, M.; Paschali, E.; Raptopoulou, C.; Terzis, A.; Chiotellis,
E. In Technetium and Rhenium in Chemistry and Nuclear Medicine
4; Nicolini, M., Bandoli, G., Mazzi, U., Eds.; SGE: Padova, 1995; p
409. (e) Papadopoulos, M.; Pirmettis, I.; Raptopoulou, C.; Terzis, A.;
Chiotellis, E. In Technetium and Rhenium in Chemistry and Nuclear
Medicine 4; Nicolini, M., Bandoli, G., Mazzi, U., Eds.; SGE: Padova,
1995; p 223. (f) Pirmettis, I.; Papadopoulos, M.; Mastrostamatis, S.;
Raptopoulou, C.; Terzis, A.; Chiotellis, E. Inorg. Chem. 1996, 35,
1685.
(5) Deutsch, E.; Libson, K.; Vanderheyden, J.-L. In Technetium and
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G., Mazzi, U., Eds.; Raven Press: New York, 1990; p 119.
S0020-1669(96)00416-8 CCC: $12.00 © 1996 American Chemical Society

7378 Inorganic Chemistry, Vol. 35, No. 25, 1996
Papadopoulos et al.
Chart 1
1
Complete assignments of H and 13C NMR resonances were
made and the crystal structures were determined by X-ray
crystallography.
Results and Discussion
Synthesis. Three methods were employed for the synthesis
of the complexes based on the ligand exchange reaction using
ReO(eg)2 (eg ) ethylene glycol), ReOCl3(PPh3)2, or Re(V)-
citrate as precursor (see Experimental Section, methods A, B,
and C) in the presence of equimolar quantities of L1H2 and
L2H. ReO(eg)2 and Re(V)-citrate were used in situ as formed
-
either by ligand exchange reaction of ReOCl4 and ethylene
-
glycol or by reduction of ReO4 by Sn2+ in citric acid. The
latter method is commonly used to prepare rhenium radiophar-
maceuticals since the starting material of radioactive rhenium
-
is ReO4
.
In all three methods, reaction products were extracted in
dichloromethane and isolated by fractional recrystallization from
CH2Cl2/MeOH. The major product, in all cases, was the syn
isomer as demonstrated by crystal structure analysis. HPLC
detection (C-18 RP column using 85/15 methanol/water as the
mobile phase and a flow rate of 1 mL/min) of the crude reaction
mixture from the A and B methods revealed the presence of a
small amount of an additional complex. This was successfully
isolated from the reaction mixture from method A and was
identified as the anti isomer by X-ray crystallography. HPLC
analysis of the reaction mixture from method C showed the
formation of only the syn isomer.
The syn isomer was retained longer on the C-18 column
(Figure 1), and the ratio syn/anti isomer as calculated by HPLC
integration was 25/1. The results are consistent with those of
the corresponding technetium isomers previously prepared with
this ligand system.2f
Both complexes gave correct elemental analysis and were
characterized by IR, UV-vis, and NMR spectroscopy. They
are soluble in acetone, dichloromethane, and chloroform, slightly
soluble in methanol or ethanol, and insoluble in ether, pentane,
and water. They are stable in the solid state as well as in organic
solutions (for a period of months) as shown by HPLC and NMR.
Their stability is not affected by the presence of air or moisture.
The infrared spectra of the compounds exhibit strong RedO
stretching bands at 946 cm-1 for the syn and 963 cm-1 for the
anti isomer. These values are consistent with those reported
for several other well-characterized monooxo complexes of
rhenium.7 The RedO stretch in each isomer was approximately
20 cm-1 higher than the TcdO stretch in the corresponding
oxotechnetium isomers.2f This shift to higher frequencies from
Figure 1. HPLC profiles: (A) UV trace at 254 nm of complex 2 (anti
isomer); (B) UV trace at 254 nm of complex 1 (syn isomer). The UV-
vis spectra of both complexes are shown in the insets. (C) γ-trace of
the reaction mixture of the 186Re preparation (tracer level).
TcdO to RedO complexes has also been reported for other
ligand systems, like BAT and MAMA.6f,7a The electronic
absorption spectra of the complexes were determined during
HPLC analysis by using the photodiode array detector. The
UV-vis spectra of the syn isomer are characterized by an
intense band at 426 nm, while the anti isomer is characterized
by an intense band at shorter wavelength (350 nm).
Complexes were prepared at the tracer level by using 186Re-
citrate as precursor. The labeling yield was over 80% as
calculated by organic solvent extraction of the aqueous reaction
mixture. HPLC analysis has shown the formation of two
complexes in a ratio 25/1 with the major product having the
longest retention time (Figure 1). When mixed samples of
complexes prepared at the tracer and carrier levels were injected
on the HPLC column, they eluted with identical retention times
as witnessed by simultaneous radioactivity (tracer) and UV-
vis detection (Figure 1). This indicates that the same chemical
species are formed at the carrier and tracer levels.
X-ray Crystallographic Studies. An ORTEP diagram of
compound 1 is given in Figure 2, and selected bond distances
and angles are given in Table 1. Complex 1 is the syn isomer
where the coordination geometry around rhenium is distorted
trigonal bipyramidal. The basal plane is formed by the sulfur
atoms of the tridentate ligand and the oxo group, while the apical
positions are occupied by the remaining nitrogen atom of the
ligand and the monodentate thiol. The calculated trigonality
index, τ, is 0.62.8 Rhenium is slightly displaced out of the basal
(6) (a) Epps, L.; Burns, H. D.; Lever, S. Z.; Goldfarb, H. W.; Wagner, H.
N. Appl. Radiat. Isotop. 1987, 36, 661. (b) Kung, H. G.; Guo, Y. Z.;
Yu, C. C.; Billings, J.; Subramanyam, V.; Calabrese, J. J. Med. Chem.
1989, 32, 433. (c) Lever, S. Z.; Baidoo, K. E.; Mahmood, A. Inorg.
Chim. Acta 1990, 176, 183. (d) Rao, T. N.; Adhikesavalu, D.;
Camerman, A.; Fritzberg, A. R. J. Am. Chem. Soc. 1990, 112, 5798.
(e) Francesconi, L. C.; Graczyk, G.; Wehrli, S.; Shaikh, N.; McClinton,
D.; Liu, S.; Zubieta, J.; Kung, H. F. Inorg. Chem. 1993, 32, 3114. (f)
O’Neil, J.; Wilson, S.; Katzenellenbogen, J. Inorg. Chem. 1994, 33,
319.
(7) (a) Mahmood, A.; Baidoo, K. E.; Lever, S. Z. In Technetium and
Rhenium in Chemistry and Nuclear Medicine 3; Nicolini, M., Bandoli,
G., Mazzi, U., Eds.; Raven Press: New York, 1990; p 119 (b) Oˆ isato,
F.; Refosco, F.; Mazzi, U.; Bandoli, G.; Nikolini, M. Inorg. Chim.
Acta 1991, 189, 97. (c) Jackson, T.; Kojima M.; Lambrecht, R. M.
Aust. J. Chem. 1993, 46, 1093.
(8) Addison, A. W.; Rao, T. N.; Reedijk, J.; Rijn, J.; Verschoor, G. C. J.
Chem. Soc., Dalton Trans. 1984, 1349.

Syn-Anti Isomerism in ReO[SN(R)S][S]
Inorganic Chemistry, Vol. 35, No. 25, 1996 7379
Figure 3. ORTEP diagram of complex 2, with 50% thermal probability
ellipsoids showing the atomic labeling scheme.
Figure 2. ORTEP diagram of complex 1, with 50% thermal probability
ellipsoids showing the atomic labeling scheme.
oxo group. The two chelating five-membered rings exist in the
envelope form where, in both cases, N1 is the “flap” atom and
is displaced by 0.86 and 0.89 Å from the best mean plane of
the remaining atoms (i.e., Re, S2, C4, and C3 and Re, S1, C1,
and C2, respectively). The dihedral angles formed by the
chelating agent of the coordinated atoms are 40.7° and 37.3°
for S1-C1-C2-N1 and S2-C4-C3-N1, respectively. The
bond length Re-S3 is 2.285(3) Å, which is slightly shorter than
the corresponding bond distances between rhenium and S1 and
S2 belonging to the tridentate ligand [Re-S1 ) 2.308 Å, Re-
S2 ) 2.297(3) Å].
In conclusion, the following remarks should be made: In the
case of the anti isomer, 2, where the SNS donor set of the
tridentate ligand is coordinated in the basal plane of the distorted
square pyramid, the Re-S1 and Re-S2 bond lengths [2.308-
(3), 2.297(3) Å] are lengthened with respect to Re-S3 [of the
monodentate thiol, 2.285(3) Å] and that of Re-N1 is shortened
[2.15(1) Å]. In the case of the syn isomer, 1, the opposite is
observed; Re-S3 and Re-N1 [2.309(2) and 2.218 Å, respec-
tively] are lengthened as a consequence of occupying the apical
positions, while the bond lengths Re-S1 and Re-S2 [2.279-
(2) and 2.275(2) Å, respectively] in the equatorial plane are
shortened. The bond length of the doubly bonded oxo group
remains unchanged at ca. 1.69 Å in both cases (i.e., in
coordination in the equatorial plane of the distorted trigonal
bipyramid or in the apical position of the distorted square
pyramid). Differences between the two isomers are also
observed in the dihedral angles between the atoms of the
chelating skeleton of the tridentate ligand. In the syn isomer,
1, the torsion angles S1-C1-C2-N1 and S2-C4-C3-N1 have
the same sign and are greater than those in the anti isomer, 2
(51.4°/49.4° and -40.7°/37.3°, respectively).
As already mentioned, the characteristic difference between
1 and 2 is the orientation of the N1 substituent (i.e., C5) toward
or away from the oxo group, respectively. This fact is reflected
by the dihedral angles around N1, where two differences are
seen: in the syn isomer, 1, the torsion angles C2-N1-C3-C4
and C4-C3-N1-C5 are 70.6° and -166.3°, respectively,
whereas in the anti isomer, 2, these dihedral angles are -175.2°
and 64.0°, respectively. This indicates an interchange in the
positions of atoms C2 and C5 in the tetrahedron around N1 in
the process of formation of the syn or anti isomer. This fact is
also indicated by the interatomic distances between O1 and C2
and C5 in the two isomers: in the syn isomer, 1, O1‚‚‚C5 )
2.90 Å and O1‚‚‚C2 ) 4.13 Å, while in the anti isomer, 2,
O1‚‚‚C5 ) 4.52 Å, and O1‚‚‚C2 ) 3.61 Å.
Table 1. Selected Bond Distances (Å) and Angles (deg)
1
2
Re-O1
Re-S1
Re-S2
Re-S3
Re-N1
1.696(5)
2.279(2)
2.275(2)
2.309(2)
2.218(8)
1.694(8)
2.308(3)
2.297(3)
2.285(3)
2.15(1)
O1-Re-S1
O1-Re-S2
O1-Re-S3
O1-Re-N1
S1-Re-S2
N1-Re-S3
S1-Re-N1
N1-Re-S2
S2-Re-S3
S3-Re-S1
117.5(2)
120.1(2)
105.2(2)
95.8(2)
121.8(1)
158.8(2)
83.8(2)
83.3(2)
88.45(8)
84.02(9)
107.9(3)
107.7(3)
106.6(4)
112.2(4)
143.8(1)
141.1(3)
81.2(3)
79.6(3)
91.7(1)
84.3(1)
plane by 0.087 Å toward the monodentate thiol. The two
chelating five-membered rings exist in the envelope form where
the “flap” atoms are C2 and C3, which are displaced by 0.64
and 0.61 Å from the best mean plane of the remaining atoms
(i.e., Re, S1, C1, and N1 and Re, S2, C4, and N1, respectively).
The dihedral angles formed by the chelating atoms of the
tridentate ligand are 51.4° and 49.4° for S1-C1-C2-N1 and
S2-C4-C3-N1, respectively. The bond distances and angles
observed in the coordination sphere are in agreement with those
found in other oxorhenium complexes with distorted trigonal
bipyramidal coordination mode. The bond length Re-S3
[2.309(2) Å] is slightly longer than that found between rhenium
and the sulfur atoms of the tridentate ligand [Re-S1 ) 2.279-
(2) Å, Re-S2 ) 2.275(2) Å]; the opposite was found for the
anti isomer. The bond angles between atoms of the basal plane
are close to the ideal value of 120° while the angle S3-Re-
N1 is 158.8(2)°, indicating the distortion of the trigonal
bipyramid.
An ORTEP diagram of compound 2 is shown in Figure 3,
and selected bond distances and angles are given in Table 1.
As shown in Figure 3, the complex is the anti isomer in which
the coordination geometry of rhenium is distorted square
pyramidal with the oxo group occupying the apical position.
The calculated trigonality index, τ, is 0.05. The basal plane of
the square pyramid is formed by the SNS donor set of the
tridentate ligand and the sulfur atom of the monodentate thiol.
Rhenium is displaced 0.72 Å out of the basal plane toward the

7380 Inorganic Chemistry, Vol. 35, No. 25, 1996
Papadopoulos et al.
Table 2. 1H Chemical Shifts δH (ppm) for Complexes 1 and 2 in
CDCl3 at 298 K (25 °C)
1
2
1
2
H1 endo
H1 exo
3.57c
2.85c
3.43c
2.78c
3.43c
2.78c
3.57c
2.85c
3.40c
3.40c
3.80c
4.33c
3.72c
4.30c
3.50c
3.60c
H5b
3.92
3.92
2.87
2.58
1.07
7.55
6.91
3.83
2.25c
2.35c
2.57
2.43
1.00
7.51
6.95
3.84
H5′ b
H2 endoa
H2 exoa
H3 endoa
H3 exoa
H4 endoa
H4 exoa
H6
H7 (H9)
H8 (H10)
H12 (H16)
H13 (H15)
H17
a Resonances appear broad due to chemical exchange between
protons H1/H4 and H2/H3. b Protons on C5 of the side chain (H5 and
H5′) are also exchanging due to the decreased mobility of the chelated
backbone. In complex 1 they appear as a broadened triplet, while in
complex 2 they appear as two separate multiplets. c Chemical shifts of
overlapping multiplets were defined from the correlation peaks of the
2D experiments.
Figure 4. 13C spectra (range δC 71.1-4.9) of complexes 1 (A) and 2
(B) in CDCl3 at 298 K.
Table 3. 13C Chemical Shifts δC (ppm) for Complexes 1 and 2 in
CDCl3 and at 298 K (25 °C)
1
2
1
2
C1a
42.04
62.99
62.99
42.04
61.26
48.21
46.99
39.38
65.60
65.21
38.84
50.53
46.02
47.06
C8 (C10)
C11
C12 (C16)
C13 (C15)
C14
11.74
144.90
134.54
113.56
158.46
55.24
11.79
140.97
134.60
113.65
158.91
55.25
C2a
C3a
C4a
C5
C6
C7 (C9)
C17
a Carbons C1/C4 and C3/C4 are in chemical exchange. In complex
1 at 298 K they are above coalescence and appear broad, while in
complex 2 they all appear separately (Figure 4).
NMR Studies. The NMR study of syn and anti stereoisomers
of the 3+1 type of complex is of great interest since it provides
the opportunity to study the effect of the direction of the free
chain on the appearance of the NMR spectra as well as on the
1
fluxional mobility of the coordinated SNS backbone. The H
and 13C chemical shifts for complexes 1 and 2 in CDCl3 at 298
K are given in Tables 2 and 3. Diastereotopic protons on the
chelated backbone are differentiated according to their orienta-
tion as endo (close to oxygen) and exo (remote from oxygen).
At room temperature, exchange occurs between the S1-C1-
C2-N and S2-C3-C4-N parts of the complexes due to the
fluxional mobility of the chelated backbone. Proton resonances
appear broad, and the great degree of overlap makes the
observation of exchange phenomena in proton spectra very
difficult. Carbon spectra are more informative. In the 13C
spectrum of the syn isomer at 298 K, exchanging carbons C1/
C4 and C2/C3 are above the coalescence temperature and appear
as one broad resonance (Figure 4A). In the 13C spectrum of
the anti isomer at the same temperature, exchanging carbons
C1/C4 and C2/C3 appear as separate signals, indicating that
ring inversion is slow on the NMR time scale (Figure 4B). The
relative height of the peaks of the exchanging carbons indicates
that the populations of the diastereomeric conformations are
equal. Calculation of the ∆Gq for conformational inversion of
the two chelated rings was based on the temperature dependence
of the carbon spectra. From the coalescence temperatures of
C1/C4 and C2/C3 and the difference in chemical shifts in the
Figure 5. Phase-sensitive NOESY spectrum of complex 1 (range δH
4.13-2.41) in CDCl3 at 298 K. Only positive levels are plotted.
mobility. However, no interconversion of the two isomers or
decomposition of any kind was noted.
1
Assignment of H and 13C spectra was based on COSY,
HETCOR, and NOESY spectra as has been previously reported
from our laboratory on technetium complexes.2bc,9 Differentia-
tion of endo from exo protons was based on NOE correlation
peaks. Specifically, in the case of the syn isomer, NOE
correlation peaks are expected between the protons on the side
chain on nitrogen and the endo protons of the chelated backbone
(Figure 5), while in the case of the anti isomer they are expected
between the side chain and the exo protons (Figure 6).
As can be seen from Table 2, the syn isomer follows the trend
consistently reported in the literature,2bc,6cef,9,10 according to
which the endo protons appear downfield compared to the exo
ones. The difference in chemical shifts between the exo and
endo protons is 0.6 -0.7 ppm and is commonly attributed to
q
absence of exchange, the average ∆Gc was found to be 13.7
OÅ 0.1 kcal/mol for complex 1 and 15.9 ( 0.1 kcal/mol for
complex 2. At 298 K, in CDCl3, conformational inversion of
the syn isomer is 36 times faster than that of the anti.
(9) Papadopoulos, M. S.; Pelecanou, M.; Pirmettis, I. C.; Spyriounis, D.;
Raptopoulou, C. P; Terzis, A.; Stassinopoulou, C. I.; Chiotellis, E.
Inorg. Chem. 1996, 35, 4478.
(10) (a) John, C. S.; Francesconi, L. C.; Kung, H. F.; Wehrli, S.; Graczyk,
G.; Carroll, P. Polyhedron 1992, 11, 1145. (b) Rao, T. N.; Brixner,
D. I.; Srinivasan, A.; Kasina, S.; Vanderheyden, J.-L.; Wester, D. W.;
Fritzberg, A. R. Appl. Radiat. Isotop. 1991, 42, 525.
1H spectra of complexes 1 and 2 were also obtained in the
range 25-85 °C in toluene-d8. As the temperature was raised,
proton multiplet peaks became sharper, indicating increased

Syn-Anti Isomerism in ReO[SN(R)S][S]
Inorganic Chemistry, Vol. 35, No. 25, 1996 7381
coordinated sulfur may also be operating. According to this
hypothesis, the different arrangement of the tridentate ligand
about the RedO or TcdO core in the syn and anti isomers
would modify the relative contributions of each mechanism and
would account for the differences observed between the syn and
anti isomers.
1
It is noted that H and 13C chemical shifts do not change
significantly on going from oxorhenium to oxotechnetium,2b,f
indicating structural similarity between RedO and TcdO
analogues. Differences are observed, however, in the mobility
of the chelated backbone, with RedO analogues being less
flexible than TcdO. For comparison purposes, the ∆Gq for
conformational inversion of the syn complex of TcdO in CDCl3
was calculated by the same method as mentioned earlier and
was found to be 12.0 kcal/mol compared to the 13.9 kcal/mol
of the RedO analogue. As a result, the chelated moieties
S1sC1sC2sN and S2sC4sC3sN of the TcdO syn complex
give identical proton and carbon spectra at 298 K due to
motional averaging of the different conformations on the NMR
time scale,2b in contrast to the RedO complex, which, at the
same temperature, is in slow exchange.
Conclusions. The simultaneous action of the tridentate N,N-
bis-(2-mercaptoethyl)- N′,N′-diethylethylenediamine and the
monodentate 4-methoxythiophenol on a suitable Re(O) precursor
results in the formation of two isomers (syn and anti) due to
the different orientation of the N substituent with respect to the
RedO. The syn isomer is preferably formed, while the anti
isomer forms in small amounts. X-ray crystallography and
NMR data show that the complexes have the same structure in
the solid phase and in solution. Under the conditions employed
during synthesis and spectral studies, no interconversion of the
two isomers was noted. The syn isomer has a trigonal
bipyramidal geometry, whereas the square pyramidal geometry
is adopted by the anti isomer. NMR studies demonstrated that
the direction of the side chain greatly influences the appearance
of the spectra and the fluxional mobility of the SNS backbone.
The isomeric set was also formed in high yield at the tracer
level using 186ReO-citrate as precursor. The identity of 186Re
complexes was determined by comparative HPLC studies with
authentic reference samples at the carrier level. This study
provides information on the [SNS][S] mixed-ligand system,
which should be useful in the preparation and characterization
of biologically significant molecules labeled with 186/188Re.
Figure 6. Phase-sensitive NOESY spectrum of complex 2 (range δH
4.54-2.98) in CDCl3 at 298 K. Only positive levels are plotted.
Figure 7. 1H NMR spectrum of the TcdO analogue of complex 2
(range δH 4.90-0.72) in CDCl3 at 298 K.
the anisotropic effects of the RedO and TcdO core.6c,e,f,10 The
situation is very different with the anti isomer 2. First of all,
the decreased mobility of the chelated backbone makes the
geminal protons on C5 diastereotopic, appearing as two mul-
tiplets at δH 2.35 and 2.25. On the average, they are shifted
upfield by 1.62 ppm compared to the corresponding protons of
the syn isomer. Carbon C5 also appears shifted upfield by 10.7
ppm compared to the corresponding carbon of the syn isomer
(Figure 4). Since carbon C5 and its protons are now at the exo
face of the molecule, the upfield shift is consistent with that
usually observed. Most important is the fact that this trend is
not followed by protons C1, C2, C3, and C4 of the chelated
backbone. The presence of NOE correlation peaks between the
multiplet at δH 2.57 belonging to protons on C6 and the most
downfield multiplets at δH 4.33 and 4.30 (Figure 6) indicates
that these peaks belong to the H2/H3 exo protons. Another
interesting point is that exo and endo protons on C1 have the
same chemical shift despite their different orientations with
respect to the RedO core (Table 2). The TcdO analogue2f of
complex 2 displays analogous behavior (Figure 7): the H2/H3
exo protons appear at δH 4.3, the H2/H3 endo protons are at δH
4.0, and the H1/H4 endo and exo protons are lumped together
at δH 3.5.
Experimental Section
Materials and Methods. Caution!!! Rhenium-186 is a â- and
γ-emitter and special precautions should be taken. IR spectra were
recorded as KBr pellets in the range 4000-500 cm-1 on a Perkin-
Elmer 1600 FT-IR spectrophotometer and were referenced to polysty-
rene. The NMR spectra were recorded in deuteriochloroform on a
Bruker AC 250E spectrometer. Elemental analyses were performed
on a Perkin-Elmer 2400/II automatic analyzer. High-performance liquid
chromatography (HPLC) analysis was performed on a Waters chro-
matograph equipped with a 600E delivery system and a µ-Bondapak
C-18 column using 85% methanol as the mobile phase at a 1.0 mL/
min flow rate. Rhenium complexes were detected by a photodiode
array detector (Waters 991 PDA) recording the UV-vis spectrum of
the eluting complexes and a Beckman 171 radioisotope detector.
All laboratory chemicals were reagent grade. The 4-methoxy-
thiophenol used as coligand was purchased from Fluka. The tridentate
ligand was synthesized by reaction of the N,N-dimethylethylenediamine
with ethylene sulfide in an autoclave at 110 °C as described previously,
and the compound was purified by vacuum distillation.11 ReOCl3-
(PPh3)2 was prepared according to the literature,12 while precursors ReO-
These data on the anti isomers are the first example in the
literature of NMR studies of oxorhenium and oxotechnetium
complexes in which exo protons of the chelated backbone do
not appear upfield compared to their endo geminals. Therefore,
we are forced to reconsider the role of the oxorhenium and
oxotechnetium cores as the sole cause of the observed magnetic
anisotropy. Other mechanisms such as the chemical bond
anisotropies of the side chain or the effect of the lone pairs on
(11) Corbin, J. L.; Miller, K. F.; Pariyadath, N.; Wherland, S.; Bruce, L.
A.; Stiefel, E. I. Inorg. Chim. Acta. 1984, 90, 41.
(12) Chatt, J.; Rowe, G. A. J. Chem. Soc. 1962, 4019.

7382 Inorganic Chemistry, Vol. 35, No. 25, 1996
Papadopoulos et al.
(eg)2 and Re(O)-citrate were generated in situ by known methods13
as described in detail in the following.
Table 4. Summary of Crystal, Intensity Collection, and Refinement
Data
Synthesis of ReO[(C2H5)2NCH2CH2N(CH2CH2S)2][SC6H4OCH3]
1
2
from [ReO(eg)2]-, Method A. The rhenium glycolate anion,
14
formula
FW
C17H29N2O2S3Re
575.80
C17H29N2O2S3Re
575.80
[ReO(eg)2]-, was prepared from 125 mg (0.2 mmol) of Bu4NReOCl4
and 1.0 mL of ethylene glycol in 15 mL of EtOH in situ. To this
solution were added 45 mg (0.2 mmol) of N,N-bis(2-mercaptoethyl)-
N′,N′-diethylethylenediamine (L1H2) and 28 mg (0.2 mmol) of 4-meth-
oxythiophenol (L2H) in 1.0 mL of dichloromethane and stirred at room
temperature for 30 min. A green solid immediately precipitated from
the reaction mixture. Volatiles were carefully removed under reduced
pressure. The pH of the residue was adjusted to 9 with 0.5 N NaOH
and the mixture was extracted two times with dichloromethane.
Analysis of the solution by HPLC (C-18 RP column using 85/15
methanol/water as the mobile phase and 1 mL/min flow rate)
demonstrated the formation of two complexes in a ratio of 25/1. The
combined organic extracts were dried over MgSO4, the volume was
reduced to 5 mL by rotary evaporation at room temperature, and 5 mL
of MeOH was added. Slow evaporation of the solvents at room
temperature afforded the major product of the reaction as a green solid
(1, syn isomer, 50% yield). The minor complex was separated as an
orange solid from the filtrate upon standing at -20 °C for several days
(2, anti isomer, 2% yield). Crystals suitable for X-ray crystallography
were obtained by recrystallization from EtOH/CH2Cl2 for both products.
1 (syn): Rf ) 0.40 (silica gel, 2/1/1 benzene/CH2Cl2/CH3OH); FT-
IR (cm-1, KBr pellet) 946 (RedO). Anal. Calcd for C17H29N2O2S3-
Re: C, 35.46; H, 5.08; N, 4.87; S, 16.70. Found: C, 35.35; H, 4.76;
N, 4.54; S, 16.32.
a (Å)
b (Å)
c (Å)
â (deg)
V (Å3)
Z
14.109(4)
7.518(2)
20.900(5)
103.07(1)
2159.4(9)
4
1.771/1.75
P21/n
298
9.3850(7)
27.979(2)
8.3648(6)
99.86(1)
2163.9(3)
4
1.767/1.75
P21/n
298
5.918
Mo KR, 0.7107
1.64
4062/3795
3747/241
1.141
D
calcd/Dmeasd (Mg m-3
)
space group
temp (K)
abs coeff (µ, mm-1
wavelength
)
5.930
Mo KR, 0.71073
1.81
max abs correction mode
reflections collected/unique 4130/4009
data used/parameters
goodness-of-fit on F2
R indicesa
3996/283
1.069
R1 ) 0.0661,
R1 ) 0.0528,
wR2 ) 0.1742b
wR2 ) 0.1349b
a I > 2σ(I), 3599 reflections for 1, 2815 reflections for 2; R1 based
2
on F’s, wR2 based on F2. b R1 ) ∑||Fo| - |Fc||/∑|Fo|; wR2 ) (∑[w(Fo
- Fc2)2]/∑[w(Fo )2])1/2
.
2
mL portions of CH2Cl2. The combined organic extracts were dried
over MgSO4 and filtered. Analysis of the mixture performed by
reversed-phase HPLC 85/15 methanol/water, flow rate 1 mL/min)
showed a major radioactive peak (>95%) with a retention time of 8
min, while a second radioactive peak (<3%) was detected at 5.5 min.
The identity of 186Re complexes was determined by comparative HPLC
studies, using as reference samples the complexes isolated at the carrier
level.
X-ray Crystal Stucture Determination. A green crystal of the
syn isomer, 1, with dimensions 0.10 × 0.50 × 0.50 mm was mounted
in air, and diffraction measurements were made on a Crystal Logic
Dual Goniometer diffractometer using graphite monochromated Mo
radiation. An orange crystal of the anti isomer, 2, (0.08 × 0.40 ×
0.50 mm), was mounted in air, and data collection was performed on
a P21 Nicolet diffractometer upgraded by Crystal Logic using Zr-filtered
Mo radiation. Unit cell dimensions were determined and refined by
using the angular settings of 25 automatically centered reflections in
the range 11 < 2θ < 23 and they appear in Table 4. Intensity data
were recorded using a θ-2θ scan. Three standard reflections monitored
every 97 reflections showed less than 3% variation and no decay.
Lorentz, polarization, and ψ-scan absorption corrections were applied
using Crystal Logic software. The structures were solved by direct
methods using SHELXS-86 and refined by full-matrix least-squares
techniques on F2 with SHELXL-93.15
1: 2θ(max) ) 51°; scan speed ) 3.5°/min; scan range ) 2.5 plus
a1a2 separation; data collected/unique/used, 4130/4009 (Rint ) 0.0122)/
3996; 283 parameters refined; for all data R1/wR2/GOF, 0.0757/0.1901/
1.110; [∆/σ]max ) 0.100; [∆F]max/[∆F]min ) 2.868/2.720 e/Å3 in the
vicinity of the heavy metal; the hydrogen atoms of the methyl groups,
the phenyl group, and the methylene corresponding to C1 and C3 were
introduced at calculated positions as riding on bonded atoms; the rest
were located by difference maps and are refined isotropically.
2: 2θ(max) ) 50°; scan speed ) 3.0°/min; scan range ) 2.5 plus
a1a2 separation; data collected/unique/used, 4062/3795 (Rint ) 0.0330)/
3747; 241 parameters refined; for all data R1/wR2/GOF, 0.0888/0.2798/
1.785; [∆/σ]max ) 0.004; [∆F]max/[∆F]min ) 3.050/-2.449 e/Å3 in the
vicinity of the heavy metal; all hydrogen atoms were introduced at
calculated positions as riding on bonded atoms and their positions were
refined isotropically.
2 (anti): Rf ) 0.45 (silica gel, 2/1/1 benzene/CH2Cl2/CH3OH); FT-
IR (cm-1, KBr pellet) 963 (RedO). Anal. Calcd for C17H29N2O2S3-
Re: C, 35.46; H, 5.08; N, 4.87; S, 16.70. Found: C, 35.20; H, 5.00;
N, 4.96; S, 16.88.
Synthesis from ReOCl3(PPh3)2, Method B. To a stirred suspension
of trichlorobis(triphenylphosphine)rhenium(V) oxide (166 mg, 0.2
mmol) in methanol (10 mL) was added 1 N CH3COONa in methanol
(2 mL, 2 mmol). A mixture of N,N-bis(2-mercaptoethyl)-N′,N′-
diethylethylenediamine (L1H2) (45 mg, 0.2 mmol) and 28 mg (0.2
mmol) of 4-methoxythiophenol (L2H) was added under stirring. The
solution was refluxed until the green-yellow color of the precursor
turned to dark green. After being cooled to room temperature, the
reaction mixture was diluted with CH2Cl2 (30 mL) and then washed
with water. The organic layer was separated from the mixture and
dried over MgSO4. The volume of the solution was reduced to 5 mL
and then 5 mL of methanol was added. Analysis of the solution by
HPLC (C-18 RP column using 85/15 methanol/water as the mobile
phase and a flow rate of 1 mL/min) demonstrated the formation of
two complexes in a ratio of 25/1. Only the major product was isolated
as a green solid. Yield: 45%.
Synthesis from ReO-citrate, Method C. To a solution of SnCl2
(38.9 mg, 0.2 mmol) in 0.5 M citric acid (5 mL) was added 57.8 mg
(0.2 mmol) of KReO4. To this mixture were added 45 mg (0.2 mmol)
of L1H2 and 28 mg (0.2 mmol) of L2H in 1 mL of dichloromethane
dropwise and stirred at room temperature for 30 min. The pH was
adjusted to 9 with 0.5 N NaOH and the mixture was extracted with
CH2Cl2. Analysis of the organic phase by HPLC (C-18 RP column
eluted by 85/15 methanol/water at a flow rate of 1 mL/min) demon-
strated the formation of only one complex. Green crystals were isolated
by a procedure similar to that described earlier. Yield: 30%. IR
(KBr): 945 cm-1 (RedO).
-
Synthesis at Tracer 186Re Level. 186ReO4 (2 mCi, 1 mL) was
added to a solution of 1 mL of 0.5 M of citric acid containing 1 mg of
SnCl2. This solution was transferred in a centrifuge tube containing
equimolar quantities (0.02 mmol) of L1H2 and L2H. The mixture was
agitated in a vortex mixer and left to react at room temperature for 10
min. The pH of the reaction mixture was adjusted to 9 with 0.5 N
NaOH and the aqueous phase was extracted with two successive 1.5
(13) (a) Morgan, G. F.; Deblaton, M.; Hussein, W.; Thornback, J. R.;
Evrard, G.; Durant, F.; Stach, J.; Abram, U.; Abram S. Inorg. Chim.
Acta 1991, 190, 257. (b) Rao, T. N.; Adhikesavalu, D.; Camerman,
A.; Fritzberg, A. R. Inorg. Chim. Acta 1991, 180, 63.
(14) Lis, T.; Jezowska-Trzebiatowska, B. Acta Crystallogr., Sec. B, 1976,
33, 1248.
(15) (a) Sheldrick, G. M. SHELXS-86, Structure solVing Program; Uni-
versity of Go¨ttingen: Go¨ttingen, Germany, 1986. (b) Sheldrick, G.
M. SHELXL-93, Program of Crystal Structure Refinement; University
of Go¨ttingen, Go¨ttingen: Germany, 1993. (c) Atomic scattering factors
were taken from International Tables for X-ray Crystallography;
Kynoch Press: Birmingham, 1974; Vol. IV.

Syn-Anti Isomerism in ReO[SN(R)S][S]
Inorganic Chemistry, Vol. 35, No. 25, 1996 7383
All non-hydrogen atoms were refined anisotropically in both
structures. No extinction corrections were applied. Selected bond
distances and angles are given in Table 1.
F2 dimension, 2048 data points, 128 t1 increments, and relaxation delay
of 1 s. The experiment was optimized for J(13C,1H) ) 130 Hz. The
data were processed by applying a sine-bell (π/2 shifted) multiplication
in both dimensions and by zero-filling to 256 data points in the F1
dimension. Digital resolution was 17.0 Hz/point in the F1 dimension
and 8.7 Hz/point in the F2 dimension.
NMR Studies. The 1H (250.13 MHz) and 13C (62.90 MHz) NMR
spectra were recorded on a Bruker AC 250E spectrometer equipped
with an Aspect 3000 computer (using the DISNMR program, version
1991) and a 5 mm 13C/1H dual probe head (1H 90o pulse width ) 10.2
µs, 13C 90° pulse width ) 10.4 µs). Samples were dissolved in CDCl3
at a concentration of ca. 1-2%. High-temperature studies were
performed in toluene-d8. Except for the variable-temperature studies,
spectra were obtained at 298 K (25 °C). Chemical shifts (δ) are relative
to internal TMS.
Calculation of ∆Gq. For the variable-temperature studies, the
coalescence region for every pair of 13C resonances under investigation
was initially determined by obtaining spectra at 5° intervals. Spectra
were then obtained in the coalescence region at 0.5° intervals to
determine the coalescence temperature Tc. Complex 1: Tc is 284.0 K
for C2/C3 (∆ν in the absence of exchange ) 95.4 Hz) and 280.0 K for
C1/ C4 (∆ν in the absence of exchange ) 43.8 Hz). Complex 2: Tc is
313.0 K for C2/C3 (∆ν ) 24.2 Hz) and 315.0 K for C1/C4 (∆ν )
34.5 Hz).
1
2D H-1H shift correlated spectra (COSY) were acquired with a
spectral window of 2180 Hz, 1024 data points, 128 t1 increments, and
1 s relaxation delay between pulse cycles. The data were processed
by applying a sine-bell (nonshifted) multiplication in both dimensions
and by zero-filling to 512 data points in the F1 domain. After inspection
the final matrix (digital resolution 4.3 Hz/point) was symmetrized.
Phase-sensitive NOESY spectra were acquired with a spectral
window of 2180 Hz, 512 data points, 128 t1 increments, a mixing time
of 1 s, and a 1 s relaxation delay between cycles. The data were
processed by applying a sine-bell squared (π/2 shifted) multiplication
in both dimensions and by zero-filling to 512 data points in the F1
dimension. After inspection the final matrix was symmetrized.
2D 13C-1H shift-correlated spectra (HETCOR) were obtained with
spectral windows of 2180 Hz in the F1 dimension and 8930 Hz in the
Acknowledgment. A.T. is grateful to Mrs. A. Athanasiou
for financial support.
Supporting Information Available: Tables of crystal data, frac-
tional atomic coordinates and anisotropic thermal parameters for all
non-hydrogen atoms, fractional atomic coordinates of H-atoms, and
full bond lengths and angles (11 pages). Ordering information is given
on any current masthead page.
IC9604167