New mixed-ligand ReV complexes with bis(2-mercaptoethyl) sulfide and functionalized thioimidazolyl ligands

Article abstract of DOI:10.1002/1099-0682(200209)2002:9<2402::AID-EJIC2402>3.0.CO;2-0

The preparation of the mixed-ligand Re^V complexes [Re(O)(κ³-SSS)(κ¹-Simz)] (1), [Re(O)(κ³-SSS)(κ¹-Simz)]·HCl (2) and [Re(O)(κ³-SSS)(κ¹-SimzCOGlyGly)] (3) are described. These [3+1] type compounds are stabilized by tridentate bis(2-mercaptoethyl) sulfide (HSSSH) and by monodentate functionalized thioimidazolyl ligands. Complexes 1, 2 and 3 were fully characterized by IR and ¹H NMR spectroscopy, and by X-ray diffraction analysis in the case of 1 and 2. In complexes 1 and 2 the Re atom is five-coordinate, presenting a distorted square pyramidal coordination geometry. Based on the angular structural parameter, τ, this distortion lies towards a trigonal bipyramidal geometry (τ = 0.40, 1; τ = 0.46, 2). Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0682(200209)2002:9<2402::AID-EJIC2402>3.0.CO;2-0

FULL PAPER
New Mixed-Ligand ReV Complexes with Bis(2-mercaptoethyl) Sulfide and
Functionalized Thioimidazolyl Ligands
[a]
[a]
[a]
[a]
ˆ
˜
Elisa Palma, Joao D. G. Correia, Angela Domingos, and Isabel Santos*
Keywords: S ligands / Rhenium / Peptides / N ligands
The preparation of the mixed-ligand ReV complexes
[Re(O)(κ3-SSS)(κ1-Simz)] (1), [Re(O)(κ3-SSS)(κ1-Simz)]·HCl
(2) and [Re(O)(κ3-SSS)(κ1-SimzCOGlyGly)] (3) are described.
These [3+1] type compounds are stabilized by tridentate
bis(2-mercaptoethyl) sulfide (HSSSH) and by monodentate
functionalized thioimidazolyl ligands. Complexes 1, 2 and 3
were fully characterized by IR and 1H NMR spectroscopy,
and by X-ray diffraction analysis in the case of 1 and 2. In
complexes 1 and 2 the Re atom is five-coordinate, presenting
a distorted square pyramidal coordination geometry. Based
on the angular structural parameter, τ, this distortion lies to-
wards a trigonal bipyramidal geometry (τ = 0.40, 1; τ = 0.46,
2).
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
(1), [Re(O)(κ3-SSS)(κ1-Simz)]·HCl (2) and [Re(O)(κ3-
SSS)(κ1-SimzCOGlyGly)] (3).
The development of mixed-ligand complexes of Re and
Tc, of the so-called [3ϩ1] type, has been thoroughly invest-
igated for labeling biomolecules, namely CNS receptor li-
gands. For this purpose different tridentate ligands and
mono thiol co-ligands have been used.[1Ϫ7] This approach
can be considered to be greatly advantageous since the com-
bination of different ligands has allowed the synthesis of
complexes with a wide variety of chemical and biochemical
properties. However, in spite of this versatility they show a
remarkable in vivo reactivity against nucleophiles, namely
SH-group containing compounds like glutathione. This in-
stability arises not only from ligand-exchange reactions be-
tween the co-ligand and nucleophiles, but also from the
presence of a vacant coordination site trans to the oxo
group.[3,6] Both processes depend on the nature and the con-
centration of the tridentate and monodentate ligands. In
order to overcome this problem we studied the chemistry
of Re and Tc using the well-known tridentate ligand bis(2-
mercaptoethyl) sulfide (HSSSH) and functionalized thioim-
idazolyl molecules as co-ligands. This type of co-ligands can
coordinate through the nitrogen and sulfur atoms. This bi-
dentate coordination mode could provide complexes with
higher stability against substitution.[3,6] The functionalized
thioimidazolyl molecules will also allow the labelling of
small peptides with [99mTc(O)]3ϩ. In this paper, we report
on the synthesis and characterization of the mixed-ligand
ReV complexes, stabilized with these co-ligands, including
one bearing a dipeptide (GlyGly): [Re(O)(κ3-SSS)(κ1-Simz)]
Results and Discussion
Synthesis and Characterization of the Simz, SimzCOOH
and SimzCOGlyGly Co-Ligands
Methyl (2-mercapto-3-methylimidazol-4-yl)methanoate
(Simz) was obtained, in a fair yield (68%), by a slight modi-
fication of a previously reported method.[9] The synthetic
pathway for its preparation involves the formation of N-
formyl and C-formyl intermediates, followed by ring forma-
tion with KSCN (Scheme 1).
Scheme 1. Synthesis of the Simz co-ligand; (i) NEt3, HCOOH,
THF, reflux; (ii) NaOCH3, CH3OCHO, room temperature; (iii)
HCl, KSCN, 65Ϫ70° C
2-(Mercapto-3-methylimidazol-4-yl)methanoic
acid
(SImzCOOH) was isolated as a white precipitate in an al-
most quantitative yield (97%) by classical hydrolysis of the
Simz ester under basic conditions, followed by acidification
of the reaction solution. The compound glycylglycine (2-
[a]
´
Departamento de Quımica, ITN,
´
Estrada Nacional 10, 2686Ϫ953 Sacavem Codex, Portugal
Fax: (internat.) ϩ351Ϫ219941455
E-mail address: isantos@itn1.itn.pt
2402
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ1948/02/0909Ϫ2402 $ 20.00ϩ.50/0 Eur. J. Inorg. Chem. 2002, 2402Ϫ2407

New Mixed-Ligand ReV Complexes with Sulfur Ligands
FULL PAPER
mercapto-3-methylimidazol-4-yl)methanamide (SimzCOG- conditions, afforded the mixed-ligand complexes [Re(O)(κ3-
lyGly) was obtained by reacting [(2-mercapto-3-methylimid- SSS)(κ1-Simz)] (1), [Re(O)(κ3-SSS)(κ1-Simz)]·HCl (2) and
azol-4-yl)methyloxy]succinimide (SimzCOSucc)[10,11] with [Re(O)(κ3-SSS)(κ1-SimzCOGlyGly)] (3) (Scheme 3).
Glycylglycine (GlyGly) (Scheme 2). For the coupling reac-
tion to proceed, it is necessary of the presence of a depro-
tonating agent such as triethylamine. The compound
SimzCOGlyGly is poorly soluble in most organic solvents,
and is readily soluble in aqueous alkaline solutions only
(pH ഠ 12).
Scheme 2. Synthesis of SimzCOGlyGly; R ϭ N-succinimido; (i)
NEt3, THF, DMF, H2O, room temperature
Scheme 3. Synthesis of complexes 1, 2 and 3; (i) NEt3, CH2Cl2 (1),
CH3CN (3), reflux; (ii) CH3CN, reflux
The most important features in the IR spectra of Simz
and derivatives is the existence of strong bands in the
The neutral oxo complex 1 was obtained in a 68% yield,
after appropriate workup, by refluxing [Re(O)(SSS)Cl] with
Simz in CH2Cl2, with NEt3 as the deprotonating agent. In
this complex, the monodentate thioimidazolyl co-ligand is
1630Ϫ1765 cmϪ1 range, and medium intensity bands in the
735Ϫ760 cmϪ1 range, which are assigned to the ν(CϭO)
and ν(CϭS) stretching vibrations, respectively.
The 1H NMR spectra of Simz, SimzCOOH and
mononegative. When the reaction is run in CH3CN, and in
SimzCOSucc in CD3OD present one singlet at δ ϭ 3.81,
3.81 and 3.78 ppm, respectively, assigned to the methyl
the absence of a base, the 1H NMR spectrum of the product
obtained, after workup, indicates a mixture of three species.
group attached to one of the nitrogen atoms of the thioimi-
Two of these species are unambiguously identified as [Re(-
dazolyl ring. Simz presents another singlet at δ ϭ 3.83 ppm,
O)(SSS)Cl] and free functionalized thioimidazolyl. The
which is assigned to the methyl group of the ester. In all
1
third species presented an H NMR spectrum that is con-
spectra, one resonance assigned to the methylenic proton of
sistent with the presence of one tridentate SSS and one
the ring system can also be observed (Simz: δ ϭ 7.61 ppm;
neutral Simz ligand (1H NMR (δ, CD3CN): 10.43 (1 H, s,
SimzCOOH: δ ϭ 7.57 ppm; SimzCOsucc: δ ϭ 8.05 ppm).
br., NH), 7.84 (1 H, s, CH), 4.10Ϫ4.05 (2 H, m, CH2), 3.88
The NH proton of the thioimidazolyl ring is also observed
(3 H, s, CH3), 3.85 (3 H, s, CH3), 3.13 (2 H, m, CH2)).
when CDCl3, CD3CN or [(CD3)2SO] is used as solvent.
Recrystallization of the crude product of this reaction, from
CH3CN/hexane, led to the formation of violet crystals and
For instance, in the case of the Simz ligand, that signal ap-
pears as a broad singlet at δ ϭ 12.08 ppm in CDCl3 and at
δ ϭ 10.28 ppm in CD3CN. In the IR spectrum, the (glygly)-
to the precipitation of a blue solid. The blue solid was iden-
1
tified by H NMR spectroscopy as [Re(O)(SSS)Cl]. The X-
functionalized thioimidazolyl ligand (SimzCOGlyGly) pre-
ray diffraction analysis of the violet crystals allowed the
formulation of complex 2, where the Simz is not depro-
tonated and is neutral. These crystals, after being washed
sents two strong bands at 1630 cmϪ1 and 1715 cmϪ1, as-
signed to the ν(CϭO) stretching vibrations of the amide
functionalities and of the free carboxylic acid of the dipept-
with CH3CN to remove any [Re(O)(SSS)Cl] present, were
ide. A characteristic medium band at 760 cmϪ1 also ap-
analyzed by NMR spectroscopy. The spectrum was ident-
pears, which is assigned to the ν˜(CϭS) stretching vibration.
ical to the one observed for the crude product. This result
can only be explained by assuming that in solution 2 disso-
1
The H NMR spectrum in [(CD3)2SO] of this ligand com-
pares well with the above mentioned thioimidazolyl derivat-
ciates as indicated in Scheme 4.
ives: a singlet at δ ϭ 3.66 ppm assigned to the methyl group,
a singlet at δ ϭ 7.58 ppm assigned to the methylenic proton
of the ring, and a broad singlet at δ ϭ 12.55 ppm assigned
to the NH group of the ring. The signals corresponding to
the dipeptide are also clearly observed: two sets of doublets
at δ ϭ 3.75 and 3.83 ppm are assigned to the CH2 groups,
and two sets of triplets at δ ϭ 8.23 and 8.60 ppm are as-
signed to the protons of the amide.
Scheme 4. (i) CH3CN
Synthesis and Characterization of the Complexes
Reactions of Simz and SimzCOGlyGly with the (chlo-
The neutral oxo complex 3 was obtained in a 60% yield
ro)oxorhenium(V) complex [ReO(SSS)Cl],[8] under different by refluxing [ReO(SSS)Cl] and SimzCOGlyGly in dry
Eur. J. Inorg. Chem. 2002, 2402Ϫ2407
2403

ˆ
E. Palma, J. D. G. Correia, A. Domingos, I. Santos
FULL PAPER
CH3CN in the presence of NEt3. Complex 1 is soluble in
chlorinated solvents and insoluble in methanol and water.
Complex 3, which bears a GlyGly moiety, is soluble in
methanol, relatively soluble in water and insoluble in chlor-
inated solvents. Both complexes 1 and 3 are air- and mois-
ture-stable.
Complexes 1, 2 and 3 present strong bands in the IR
spectra at 970 cmϪ1, which are assigned to the ν(ReϭO)
stretching vibrations. This value compares well with those
found in other compounds of the [3ϩ1] type, previously
described (930Ϫ980 cmϪ1).[7] Strong bands at 1715, 1725,
and at 1535 cmϪ1/1645 cmϪ1 are assigned to the ν(CϭO)
stretching vibrations of complexes 1, 2 and 3, respectively.
In the 1H NMR spectra of 1 and 3, four sets of multiplets
appear, which are assigned to the methylenic protons of the
tridentate ligand HSSSH; most of these signals are shifted
upfield relative to those of the corresponding free ligand.
For complex 2, the identification of all methylenic protons
of the tridentate ligand was not possible since two of the
resonances are superimposable with those of [ReO(SSS)Cl],
which is also present due to the equilibrium depicted in
Scheme 4.
Figure 2. ORTEP drawing of complex 2 with the atom numbering
scheme; thermal ellipsoids are drawn at the 30% probability level.
Hydrogen atoms were introduced in calculated positions.
3
˚
Table 1. Selected bond lengths (A) and Angles (°) for [Re(O)(κ -
SSS)(κ1-Simz)] (1), and [Re(O)(κ3-SSS)(κ1-Simz)]·HCl (2)
1
2
ReϪO(1)
ReϪS(1)
ReϪS(2)
ReϪS(3)
ReϪS(4)
S(4)ϪC(5)
1.683(8)
2.285(3)
2.367(3)
2.285(3)
2.327(3)
1.745(13)
1.673(5)
2.290(2)
2.364(2)
2.282(2)
2.345(2)
1.734(7)
The chemical shifts corresponding to the monodentate
ligand of the complexes 1 (δ ϭ 7.73, 3.85 and 3.82 ppm)
and 2 (δ ϭ 10.43, 7.84, 3.88 and 3.85 ppm) in CD3CN are
shifted downfield relative to those of the free ligand (δ ϭ
10.28, 7.45, 3.78 and 3.73 ppm) in the same solvent. The
same holds true for complex 3 in CD3OD (3: δ ϭ 7.76, 4.05,
3.94 and 3.89 ppm; SimzCOGlyGly: δ ϭ 7.51, 4.00, 3.88
and 3.79).
O(1)ϪReϪS(1)
O(1)ϪReϪS(2)
O(1)ϪReϪS(3)
O(1)ϪReϪS(4)
S(1)ϪReϪS(3)
S(3)ϪReϪS(4)
S(1)ϪReϪS(4)
S(3)ϪReϪS(2)
S(1)ϪReϪS(2)
S(4)ϪReϪS(2)
ReϪS(4)ϪC(5)
114.5(3)
100.6(3)
115.1(3)
105.3(3)
130.35(14)
87.64(12)
82.38(12)
84.25(11)
84.18(11)
154.00(11)
110.7(4)
116.6(2)
99.3(2)
115.4(2)
105.1(2)
127.86(7)
88.29(7)
81.15(7)
84.44(7)
84.76(7)
155.29(7)
110.1(2)
Crystal Structures of [Re(O)(κ3-SSS)(κ1-Simz)] (1) and
[Re(O)(κ3-SSS)(κ1-Simz)]·HCl (2): Suitable crystals for X-
ray structural analysis were obtained for complexes 1 and
2. ORTEP views are shown in Figure 1 and Figure 2, and
selected bond lengths and angles for both complexes are 3ϩ1 compounds.[1Ϫ6,12Ϫ16] The CϪS bond lengths
˚
˚
presented in Table 1.
[1.745(13) A (1), 1.734(7) A (2)] are comparable and are
similar to those found previously,[17] which range from 1.68
to 1.73 A. Additionally, provided that the values found for
˚
the best least-square planes through the atoms
˚
S(1)ϪS(2)ϪS(3)ϪS(4) (RMSD ϭ 0.218 A for 1, RMSD ϭ
˚
0.253 A for 2) show significant deviations from planarity,
we conclude that these atoms in both structures do not de-
fine a basal plane. The chloride ion is hydrogen bonded to
˚
N(1) and the distance between them [3.023(8) A] allows for
˚
the presence of a hydrogen atom [N(1)ϪH(1): 0.86 A,
˚
H(1)···Cl: 2.18 A]. The angle N(1)ϪH(1)ϪCl is 166.7°,
which can be considered to be linear. Relative to the coor-
dination positions, in both complexes (1 and 2), only one
of the axial positions is occupied by the oxo group. The
equatorial positions are defined by sulfur atoms, three from
Figure 1. ORTEP drawing of complex 1 with the atom numbering
scheme; thermal ellipsoids are drawn at the 40% probability level.
Hydrogen atoms were introduced in calculated positions.
Complex 2 is monocationic with a chloride atom as the the tridentate and dianionic ligand (SSS)2Ϫ, and a thione
counterion, while complex 1 is neutral. In both compounds sulfur atom belonging to the monodentate thioimidazolyl
the coordination geometry around the five-coordinate Rev co-ligand.
˚
atom is best described as distorted square-pyramidal, with
The ReϪS(4) bond lengths in 1 [2.327(3) A] and 2
˚
the axial ReϪO(1) bond length significantly shorter than [2.345(2) A] are comparable and typical of a monothiolate.
the ReϪL(basal) distances. The ReϭO(1) bond lengths in The ReϪS bonds within the tridentate ligand in 1 [2.285(3),
˚
˚
˚
1 [1.683(8) A] and 2 [1.673(5) A] are comparable, and are 2.367(3) and 2.285(3) A ] and 2 [2.290(2), 2.364(2) and
˚
˚
in the range (1.67Ϫ1.70 A) so far observed for this type of 2.282(2) A] compare with the values found for the same
2404
Eur. J. Inorg. Chem. 2002, 2402Ϫ2407

New Mixed-Ligand ReV Complexes with Sulfur Ligands
FULL PAPER
Table 2. Crystallographic data for complexes 1 and 2
1
2
Empirical formula
Formula mass
Crystal size, mm
Temperature, K
Crystal system
Space group
C10H15N2O3S4Re·CHCl3
645.05
0.18 ϫ 0.17 ϫ 0.17
293(2)
Monoclinic
P21/c
8.275(2)
C10H16ClN2O3S4Re
578.14
0.34 ϫ 0.18 ϫ 0.10
293(2)
Triclinic
¯
P1
˚
a, A
8.069(2)
9.935(2)
12.664(2)
96.830(10)
92.000(10)
109.80(2)
945.3(3)
2
˚
b, A
17.287(2)
14.373(3)
˚
c, A
α, deg
β, deg
γ, deg
98.37(2)
3
˚
V, A
2034.2(7)
4
2.106
6.791
3.7Ϫ56.00
5082
4896 [R(int) ϭ 0.0502]
217
Z
Density (calcd.), g·cmϪ3
Absorption coefficient, mmϪ1
2θ Range, deg
2.031
7.024
3.24Ϫ54.00
4385
4140 [R(int) ϭ 0.0201]
223
Reflections collected
Independent reflections
Parameters
Observed reflections [IϾ2σ(I)]
Final R indices [IϾ2σ(I)]
2917
3539
R1[a] ϭ 0.0637wR2[b] ϭ 0.0995
R1[a] ϭ 0.0390
wR2[b] ϭ 0.0869
1.052
Goodness-of-fit
1.087
[a]
[b]
2
2 2
2 2
2
2
2
R1 ϭ Σ||Fo| Ϫ |Fc||/ Σ|Fo|. wR2 ϭ {Σ[w(Fo Ϫ Fc ) ]/Σ[w(Fo ) ]}1/2; w ϭ 1/[σ2(Fo ) ϩ (aP)2 ϩ bP], where P ϭ (Fo ϩ 2Fc )/3.
type of bond in complexes of the 3ϩ1 type, stabilized by 1) and 110.1(2)° (for 2)] that prevents N(1) from coordinat-
SSS chelates.[1,18]
ing to the metal.
The five-membered rings, formed by the atoms Re, S(1),
C(1), C(2) and S(2) are in the twisted form in both com-
plexes. Relative to the plane [ReϪS(1)ϪS(2)], C(1) is 0.53
Concluding Remarks
˚
and 0.50 A above the plane for 1 and 2, respectively, and
˚
C(2) is Ϫ0.25 and Ϫ0.21 A below the plane for 1 and 2, re-
Using the tridentate bis(2-mercaptoethyl) sulfide ligand
and functionalized thioimidazolyl coϪligands, it was pos-
sible to isolate and characterize oxorhenium(V) complexes
of the [3ϩ1] type. The complexes are stable in solution
when the monodentate thioimidazolyl co-ligands are
monoanionic. The functionalization of the thioimidazolyl
with a dipeptide leads to a water soluble complex, which is
promising for biomedical applications.
spectively.
The five-membered rings, formed by the atoms Re, S(2),
C(3), C(4) and S(3) are in the twisted form in both com-
plexes. Relative to the plane [ReϪS(2)ϪS(3)], C(3) and C(4)
are equally far from the plane by 0.37 A in complex 1, and
in 2 are 0.30 and Ϫ0.39 A above and below the plane, re-
˚
˚
spectively.
In terms of the trigonality index, τ, the values are 0.40
and 0.46 for 1 and 2, respectively (τ ϭ 0 for a regular square
pyramid, τ ϭ 1 for a regular trigonal bipyramid).[19] Ac-
cording to the results in this work and those obtained earl- Experimental Section
ier for complexes with a SSS/S donor atom set,[1,18] the τ
values remain between 0.253Ϫ0.473. This means that the
majority of structures in this study may be classified as in- were dried and distilled prior to use, according to described proced-
General Procedures: All chemicals were of reagent grade. Solvents
ures. Methyl (2-mercapto-3-methylimidazol-4-yl) methanoate
(Simz) was prepared by a modification of a reported method and
[Re(O)(SSS)Cl] as described in the literature.[8,9] The reactions were
run in air unless otherwise indicated. 1H NMR spectra were re-
corded on a Varian Unit 300 MHz spectrometer. 1H chemical shifts
were referenced to the residual solvent resonance relative to tetra-
methylsilane. The NMR samples were prepared in CDCl3, CD3OD,
[(CD3)2SO] and CD3CN. Infrared spectra were recorded in the
range 4000Ϫ200 cmϪ1 on a PerkinϪElmer 577 spectrometer with
termediate between the square pyramidal and trigonal bi-
pyramidal limiting geometries, but in agreement with the
structural index parameter (τ) adopted, all of the structures
are described as distorted square pyramidal rather than dis-
torted trigonal bipyramidal. The major distortions from the
regular square pyramidal geometry arise from the chelate
bite angles of the tridentate ligand (see Table 2).
We also note that one of the reasons that the thioimida-
zolyl co-ligand acts as a monodentate ligand may be due to
KBr pellets. Elemental analyses were performed on
a
the existence of a wide angle [ReϪS(4)ϪC(5): 110.7(4)° (for PerkinϪElmer automatic analyser.
Eur. J. Inorg. Chem. 2002, 2402Ϫ2407
2405

ˆ
E. Palma, J. D. G. Correia, A. Domingos, I. Santos
FULL PAPER
Methyl (2-Mercapto-3-methylimidazol-4-yl)methanoate (Simz). i. Glycylglycine
(2-Mercapto-3-methylimidazol-4-yl)methanamide
Methyl N-Formylsarcosinate: Triethylamine (48 mL, 0.344 mol) and
formic acid (4.8 mL, 0.127 mol) were added to a solution of sarcos-
ine methyl ester hydrochloride (16.0 g, 0.115 mol) in THF (30 mL).
(SimzCOGlyGly): A mixture of glycylglycine (0.25 g; 1.9 mmol)
and triethylamine (0.30 mL, 2.2 mmol) in THF/H2O 3:4 (7 mL)
was added dropwise, at room temperature, to a stirred solution of
The suspension was stirred at 125° C overnight, cooled to room SimzCOSucc (0.25 g; 0.97 mmol) in THF/DMF 1:1 (4 mL). After
temperature, filtered, and the obtained solid rinsed with THF. The
filtrate was collected and the solvent evaporated to dryness. The
obtained yellow oil was dissolved in water (20 mL) and a solution
20 hours, whilst stirring at room temperature, the solvent was evap-
orated to dryness and the white solid obtained was washed with
1
water. Yield: 0.053 g (20%). H NMR (CD3OD): δ ϭ 3.79 (s, 3 H,
1
of NaOH (1 ) was added dropwise until pH ϭ 7. After extracting CH3), 3.88 (s, 2 H, CH2), 4.00 (s, 2 H, CH2), 7.51 (s, 1 H, CH). H
with CH2Cl2 (3 ϫ 20 mL), the solution was dried over magnesium
sulfate, filtered and concentrated to dryness. A white solid was ob-
tained. Yield: 8.53 g (57%). 1H NMR (δ, CDCl3) two rotamers:
2.62 (s, 3 H, NCH3), 2.77 (s, 3 H, NCH3), 3.46 (s, 2 H, CH2), 3.49
NMR [(CD3)2SO]: δ ϭ 3.66 (s, 3 H, CH3), 3.75 (d, 2 H, CH2), 3.83
(d, 2 H, CH2), 7.58 (s, 1 H, CH), 8.23 (t, 1 H, NH), 8.60 (t, 1 H,
NH), 12.55 (br. s, 1 H, NH) ppm. IR (KBr): ν˜ ϭ 3060 cmϪ1, 3220
cmϪ1, 3320 cmϪ1(m, NϪH), 1630 cmϪ1, 1715 cmϪ1 (vs, CϭO), 760
(s, 2 H, CH2), 3.79 (s, 1 H, OCH3), 3.82 (s, 1 H, OCH3), 7.76 (s, 1 cmϪ1 (m, CϭS). C9H12N4O4S (272.3): calcd. C 39.70, H 4.44, N
H, CHO), 7.83 (s, 1 H, CHO).
20.58, S 11.77; found C 38.97, H 4.32, N 20.01, S 11.18.
ii. Methyl (2-Mercapto-3-methylimidazol-4-yl)methanoate (Simz): A
solution of methyl N-formylsarcosinate (8.52 g, 65.0 mmol) in
[Re(O)(κ3-SSS)(κ1-Simz)] (1):
0.41 mmol) and triethylamine (68 µL, 0.49 mmol) in dichlorome-
A
solution of Simz (0.071 g;
methyl formate (14 mL, 0.227 mol) was added dropwise to a solu- thane (2 mL) was added dropwise, at room temperature, to a stirred
tion of sodium methoxide (4.11 g, 76.1 mmol) in distilled THF (40 solution of [Re(O)Cl(SSS)] (0.080 g; 0.21 mmol) in the same solvent
mL), at 10-15° C. The resulting mixture was stirred overnight at (9 mL). After several minutes the color of the solution turned
room temperature. The solvent was removed under vacuum and brown. The mixture was refluxed under a nitrogen atmosphere for
the residue diluted with 150 mL MeOH/H2O (1:1). The solution
was treated with activated carbon, filtered and cooled in ice. Hydro-
chloric acid (12 , 13 mL) and a solution of potassium thiocyanate
4 hours. A brown solid was obtained after evaporation of the solv-
ent and washing with methanol. Brown crystals suitable for X-ray
diffraction analysis were obtained by slow diffusion of hexane to a
(7.92 g, 81.5 mmol) in a minimum amount of water were added, solution of the complex in chloroform. Yield: 0.072 g (67%). 1H
and the resulting solution heated at 65°-70° C for 24 hours. The
precipitate formed was removed by filtration, and the solvent was
evaporated to dryness affording a white solid that corresponds to
NMR (CD3CN): δ ϭ 2.28Ϫ2.18 (m, 2 H, CH2), 3.14Ϫ3.04 (m, 2
H, CH2), 3.82 (s, 3 H, CH3), 3.85 (s, 3 H, CH3), 4.07Ϫ4.02 (m, 2
H, CH2), 4.24Ϫ4.18 (m, 2 H, CH2), 7.73 (s, 1 H, CH) ppm. IR
the pure product. Yield: 7.57 g (68%). 1H NMR (CDCl3): δ ϭ 3.84 (KBr): ν˜ ϭ 1715 cmϪ1, (vs, CϭO), 970 cmϪ1 (s, ReϭO), 740 cmϪ1
,
(s, 3 H, CH3), 3.87 (s, 3 H, CH3), 7.42 (s, 1 H, CH), 12.08 (br. s, 1
760 cmϪ1, 770 cmϪ1. C10H15N2O3S4Re·3CHCl3 (883.8): calcd. C
H, NH) ppm. 1H NMR (CD3OD): δ ϭ 3.81 (s, 3 H, CH3), 3.83 (s, 17.67, H 2.05, N 3.17 S 14.51; found C 17.52 H 1.98, N 3.08,
1
3 H, CH3), 7.61 (s, 1 H, CH) ppm. H NMR (CD3CN): δ ϭ 3.73 S 14.02.
(s, 3 H, CH3), 3.78 (s, 3 H, CH3), 7.45 (s, 1 H, CH), 10.28 (br. s, 1
[Re(O)(κ3-SSS)(κ1-Simz)]·HCl (2): A suspension of Simz (0.022 g,
H, NH) ppm. IR (KBr): ν˜ ϭ 1715 cmϪ1 (vs, CϭO), 755 cmϪ1 (m,
0.13 mmol) in CH3CN (2 mL) was added dropwise, at room tem-
perature, to a blue solution of [Re(O)Cl(SSS)] (0.050 g, 0.13 mmol)
CϭS).
(2-Mercapto-3-methylimidazol-4-yl)methanoic Acid (SImzCOOH):
Methyl (2-mercapto-3-methylimidazol-4-yl)methanoate (Simz)
in the same solvent (9 mL). The violet mixture was refluxed under
a nitrogen atmosphere for 4 hours. The solvent was evaporated, the
(6.00 g, 34.8 mmol) was dissolved in a NaOH solution (50 mL, 2.1 crude product was washed with CH3CN and, after drying under
1
). After 3 hours at room temperature, whilst stirring, HCl (3 )
vacuum, analyzed by H NMR spectroscopy. The NMR spectrum
was added dropwise until pH ϭ 1Ϫ2. A white solid precipitated indicates a mixture of three species, two of them identified as Simz
that was collected by filtration, washed with water and dried. Yield:
and [Re(O)Cl(SSS)]. Recrystallization of the crude solid from
CH3CN/hexane led to violet crystals, which were formulated as
1
5.33 g (97%). H NMR (CD3OD): δ ϭ 3.81 (s, 3 H, CH3), 7.57 (s,
1 H, CH) ppm. IR (KBr): ν˜ ϭ 1670 cmϪ1 (vs, CϭO), 755 cmϪ1 complex 2 by X-ray diffraction analysis. IR (KBr): ν˜ ϭ 1725 cmϪ1
(m, CϭS). C5H6N2O2S (158.2): calcd. C 37.97, H 3.82, N 17.71, S (vs, CϭO), 965 cmϪ1(s, ReϭO), 750 cmϪ1, 760 cmϪ1
.
20.27; found C 38.13, H 4.11, N 17.55, S 20.52.
[Re(O)(κ3-SSS)(κ1-SimzCOGlyGly)] (3): A mixture of SimzCOG-
lyGly (0.029 g, 0.11 mmol) and triethylamine (18 µL, 0.13 mmol)
in acetonitrile (2 mL) and a few drops of dry dimethylformamide
was added dropwise, at room temperature, to a stirred solution of
[(2-Mercapto-3-methylimidazol-4-yl)methyloxy]succinimide (Simz-
COSucc): N-hydroxysuccinimide (0.71 g; 6.2 mmol) was added to
a suspension of SimzCOOH (0.89 g; 5.6 mmol) in CH2Cl2 (15 mL)
in an ice bath, and the mixture was stirred for 15 minutes. On [Re(O)Cl(SSS)] (0.050 g, 0.13 mmol) in acetonitrile (9 mL). After
addition of N-(3-dimethylaminopropyl)-NЈ-ethylcarbodiimidehyd-
rochloride (1.19 g; 6.2 mmol) and after stirring for 63 hours, the
reaction was complete. The solvent was evaporated to dryness, and
the urea formed and the excess N-hydroxysuccinimide were re-
moved by washing the residue with water. The compound was then
vacuum-dried for several hours and used without further purifica-
tion. Yield: 1.35 g (95%). 1H NMR (CD3OD): δ ϭ 2.88 (s, 4 H,
several minutes the color of the solution turned brown. The reac-
tion mixture was refluxed under a nitrogen atmosphere overnight
and the solvent evaporated to dryness. The residue obtained was
extracted with methanol and a brown solid was obtained after
evaporation of the solvent. This compound was then washed with
acetonitrile and further purified by recrystallization from meth-
anol/dichloromethane. Yield: 0.044 g (64%). 1H NMR (CD3OD):
C2H2), 3.78 (s, 3 H, CH3), 8.05 (s, 1 H, CH) ppm. 1H NMR δ ϭ 2.32Ϫ2.22 (m, 2 H, CH2), 3.13Ϫ3.03 (m, 2 H, CH2), 3.89 (s,
[(CD3)3SO]: δ ϭ 2.86 (s, 4 H, C2H2), 3.66 (s, 3 H, CH3), 8.34 (s, 1 3 H, CH3), 3.94 (s, 2 H, CH2), 4.05 (s, 2 H, CH2), 4.13Ϫ4.08 (m,
H, CH), 13.21 (br. s, 1 H, NH) ppm. IR (KBr): ν˜ ϭ 1725 cmϪ1
,
2 H, CH2), 4.26Ϫ4.20 (m, 2 H, CH2), 7.76 (s, 1 H, CH) ppm. IR
1765 cmϪ1 (vs, CϭO), 735 cmϪ1 (m, CϭS). C9H9N3O4S·H2O (KBr): ν˜ ϭ 1645 cmϪ1, 1535 cmϪ1 (vs, CϭO), 970 cmϪ1 (s, Reϭ
(273.3): calcd. C 39.56, H 4.06, N 15.38, S 11.73; found C 40.02,
H 3.92, N 15.52, S 12.03.
O). C13H19N4O5S4Re·2CH2Cl2 (795.6): calcd. C 22.64, H 2.91, N
7.04, S 16.12; found C 22.69, H 2.64, N 7.32, S 16.35.
2406
Eur. J. Inorg. Chem. 2002, 2402Ϫ2407

New Mixed-Ligand ReV Complexes with Sulfur Ligands
FULL PAPER
B. A. Nock, T. Maina, D. Yannoukakos, I. C. Pirmettis, M. S.
Papadopoulos, E. Chiotellis, J. Med. Chem. 1999, 42,
1066Ϫ1075.
M. Friebe, H. Spies, W. Seichter, P. Leibnitz, B. Johannsen, J.
Chem. Soc., Dalton Trans. 2000, 2471Ϫ2475.
A. Rey, I. Pirmettis, M. Pelecanou, M. Papadopoulos, C. P.
Raptopoulou, L. Mallo, C. I. Stassinopoulou, A. Terzis, E.
[3]
X-ray Crystallographic Analysis: A brown crystal of 1 was obtained
by recrystallization from CHCl3/hexane, and a violet crystal of 2
was obtained from CH3CN/hexane. Both were mounted in thin-
walled glass capillaries. Data were collected at room temperature
on an EnrafϪNonius CAD-4 diffractometer with graphite-mon-
ochromatized Mo-Kα radiation, using a ω-20 scan mode. The crys-
tallographic data for both complexes are summarized in Table 2.
Unit cell dimensions were obtained by least-squares refinement of
the setting angles of 25 reflections with 14.85Ͻ2θϽ27.28° for 1
and 15.30Ͻ2θϽ26.87° for 2. Data were corrected for Lorentz and
polarization effects, for linear decay (for 1) and for absorption by
empirical corrections based on ψ scans.[20] The heavy atom posi-
tions were located by Patterson methods using SHELXS-86.[21] The
remaining atoms were located by successive different Fourier maps
and refined by least-squares refinements on F2 using SHELXL-
93.[22] One CHCl3 molecule of crystallization was also located in
the Fourier difference map for 1. In 2, the atoms O(2), C(3) and
C(10) are disordered over two positions rotated about the
C(7)ϪC(9) bond, which refined with site occupancy factors of 0.69
and 0.31, respectively (in the interests of clarity only one site is
shown in Figure 2). In the residual electron density of 2, the highest
peak was assumed to be an oxygen atom of a water molecule, which
presents a high thermal motion. All the non-hydrogen atoms were
refined with anisotropic thermal motion parameters and the contri-
bution of the hydrogen atoms was included in calculated positions,
(except the hydrogens of the water molecule in 2). The drawings
were made with ORTEP-3 and the calculations were performed on
a DEC α 3000 computer.[23] CCDC-178292 (1) and CCDC-178293
(2) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax:
(internat.) ϩ44Ϫ1223/336Ϫ033; E-mail: deposit@ccdc.cam.ac.uk].
[4]
[5]
´
Chiotellis, A. Leon, Inorg. Chem. 2000, 39, 4211Ϫ4218.
[6]
B. Nock, T. Maina, A. Tsortos, M. Pelecanou, C. P. Raptopou-
lou, M. Papadopoulos, H. J. Pietzsch, C. I. Stassinopoulou, A.
Terzis, H. Spies, G. Nounesis, E. Chiotellis, Inorg. Chem. 2000,
39, 4433Ϫ4441.
[7]
[8]
ˆ
J. D. G. Correia, A. Domingos, I. Santos, H. Spies, J. Chem.
Soc., Dalton Trans. 2001, 2245Ϫ2250.
T. Fietz, H. Spies, H.-J. Pietzsch, P. Leibnitz, Inorg. Chim. Acta
1995, 231, 233Ϫ236.
M. P. HaY, W. R. Wilson, W. A. Denny, Tetrahedron 2000,
56, 645Ϫ657.
M. Santimaria, T. Maina, U. Mazzi, M. Nicolini, Inorg. Chim.
Acta 1995, 240, 291Ϫ297.
A. Kramer, R. Alberto, A. Egli, I. Novak-Hofer, K. Heg-
etschweiler, U. Abram, P. V. Bernahardt, P. A. Schubiger, Bi-
oconjugate Chem. 1998, 9, 691Ϫ702.
K. P. Maresca, F. J. Femia, G. H. Bonavia, J. W. Babich, J.
Zubieta, Inorg. Chem. Commun. 1998, 1, 209Ϫ212.
F. Tisato, F. Refosco, U. Mazzi, G. Bandoli, M. Nicolini, J.
Chem. Soc., Dalton Trans. 1987, 1693Ϫ1699.
M. Pelecanou, I. C. Pirmettis, M. S. Papadopoulos, C. P. Rap-
topoulou, A. Terzis, E. Chiotellis, C. I. Stassinopoulou, Inorg.
Chim. Acta 1999, 287, 142Ϫ151.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
M. S. Papadopoulos, M. Pelecanou, I. C. Pirmettis, D. M. Spy-
riounis, C. P. Raptopoulou, A. Terzis, C. I. Stassinopoulou, E.
Chiotellis, Inorg. Chem. 1996, 35, 4478Ϫ4483.
R. Syhre, S. Seifert, H. Spies, A. Gupta, B. Johannsen, Eur. J.
Nucl. Med. 1998, 25, 793Ϫ796.
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
ˆ
R. Garcia, A. Paulo, A. Domingos, I. Santos, J. Organomet.
Chem. 2001, 632, 41Ϫ48.
K. P. Maresca, G. H. Bonavia, J. W. Babich, J. Zubieta, Inorg.
Chim. Acta 1999, 284, 252Ϫ257.
A.W. Addison, T. N. Rao, J. Reedijk, J. van Rijn, G. Verschoor,
J. Chem. Soc., Dalton Trans. 1984, 1349Ϫ1356.
C. K. Fair, MOLEN, EnrafϪNonius, Delft, The Netherlands,
1990.
G. M. Sheldrick, SHELXS-86, Program for the solution of
Crystal Structures, University of Göttingen, Germany, 1986.
G. M. Sheldrick, SHELXL-93, Program for the refinement of
crystal structures, University of Göttingen, Germany, 1993.
L. Farrugia, J. Appl. Crystallogr. 1997, 32, 837Ϫ838.
Received January 31, 2002
Acknowledgments
This work has been partially supported by POCTI/35423/QUI/99
and by COST Action B12. Elisa Palma acknowledges FCT for a
BIC grant.
[1]
K. P. Maresca, F. J. Femia, G. H. Bonavia, J. W. Babich, J.
Zubieta, Inorg. Chim. Acta 2000, 297, 98Ϫ105.
H. Spies, T. Fietz, H. J. Pietsch, B. Johannsen, P. Leibnitz, G.
[2]
Reck, D. Scheller, K. Klostermann, J. Chem. Soc., Dalton
Trans. 1995, 2277Ϫ2280.
[I02053]
Eur. J. Inorg. Chem. 2002, 2402Ϫ2407
2407