Syntheses, structures and reactivities of [CpTc(CO)3X] + and [CpRe(CO)3X]+

Article abstract of DOI:10.1002/ejic.200800258

We have synthesized the [Cp*M^III(CO)₃Br] ⁺ complexes (M = Re, ⁹⁹Tc) and studied their basic chemistry in water and in organic solvents in order to understand if these complexes could be synthons for the preparation of new Re- and ⁹⁹Tc-based cyclopentadienyl cores for (radio)pharmaceutical applications. The [Cp*M^III(CO)₃Br]Br [M = Re (1), ⁹⁹Tc (1a)] complexes were obtained in nearly quantitative yield from the reaction of the corresponding [Cp*M^I(CO)₃] with Br₂ in cold toluene. Compounds 1 and 1a are photo- and thermally unstable and undergo rapid, bromide concentration-dependent redox reactions at room temperature generating the stable [Cp*M^III(CO) ₃Br][(CO)₃M^I(μ-Br)₃M ^I(CO)₃] [M= Re (2), ⁹⁹Tc (2a)] species as main products. Reaction of 1 with AgSbF₆ gives rise to the redox-stable complex [Cp*Re^III(CO)₃-Br]SbF₃ (3). In water, 1 and 1a produces a mixture of cis/trans-[Cp*M^IIIBr ₂(CO)₂] isomers [M = Re (cis/trans-4), ⁹⁹Tc (cis/trans-4a)] via CO release. In methanol, 3 reacts with the solvent to generate the methoxycarbonyl complex trans-[Cp*Re^III(CO) ₂Br(COOCH₃)] (5). Compound 5 is stable under basic conditions. In acidic media it is converted into [Cp*Re ^I-(CO)₃] as the major product. Kinetic studies with ¹³C labelled formic acid indicate that formic acid, generated from rapid hydrolysis of methyl formate released from 5, is the reducing agent and the source of CO. Reaction of 1 with 3-fluorobenzyl alcohol (3-FBA), chosen as a simple model of fluorouracil, gives the corresponding alkoxycarbonyl complex [Cp*Re^III-(CO)₂Br(COOCH₂-C ₆H₄F)] (7). Under acidic conditions 7 rapidly releases 3-FBA to give [Cp*Re^I(CO)₃]. Compounds 2, 2a, cis-4, trans-4a and 5 were structurally characterized. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejic.200800258

FULL PAPER
DOI: 10.1002/ejic.200800258
Syntheses, Structures and Reactivities of [CpTc(CO)3X]+ and [CpRe(CO)3X]+
Fabio Zobi,[a] Bernhard Spingler,[a] and Roger Alberto*[a]
Dedicated to Prof. Dr. W. A. Herrmann on the occasion of his 60th birthday
Keywords: Rhenium / Technetium / Cyclopentadienyl ligand / Prodrug
We have synthesized the [Cp*MIII(CO)3Br]+ complexes (M =
Re, 99Tc) and studied their basic chemistry in water and in
organic solvents in order to understand if these complexes
could be synthons for the preparation of new Re- and 99Tc-
based cyclopentadienyl cores for (radio)pharmaceutical ap-
plications. The [Cp*MIII(CO)3Br]Br [M = Re (1), 99Tc (1a)]
complexes were obtained in nearly quantitative yield from
the reaction of the corresponding [Cp*MI(CO)3] with Br2 in
cold toluene. Compounds 1 and 1a are photo- and thermally
99Tc (cis/trans-4a)] via CO release. In methanol, 3 reacts with
the solvent to generate the methoxycarbonyl complex trans-
[Cp*ReIII(CO)2Br(COOCH3)] (5). Compound 5 is stable under
basic conditions. In acidic media it is converted into [Cp*ReI-
(CO)3] as the major product. Kinetic studies with 13C labelled
formic acid indicate that formic acid, generated from rapid
hydrolysis of methyl formate released from 5, is the reducing
agent and the source of CO. Reaction of 1 with 3-fluoroben-
zyl alcohol (3-FBA), chosen as a simple model of fluorouracil,
unstable and undergo rapid, bromide concentration-depend- gives the corresponding alkoxycarbonyl complex [Cp*ReIII-
ent redox reactions at room temperature generating the
stable [Cp*MIII(CO)3Br][(CO)3MI(µ-Br)3MI(CO)3] [M = Re (2),
99Tc (2a)] species as main products. Reaction of 1 with
AgSbF6 gives rise to the redox-stable complex [Cp*ReIII(CO)3-
Br]SbF6 (3). In water, 1 and 1a produces a mixture of
cis/trans-[Cp*MIIIBr2(CO)2] isomers [M = Re (cis/trans-4),
(CO)2Br(COOCH2–C6H4F)] (7). Under acidic conditions 7
rapidly releases 3-FBA to give [Cp*ReI(CO)3]. Compounds 2,
2a, cis-4, trans-4a and 5 were structurally characterized.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
blocked by η5- or η6-aromatic ring, we became interested
in extending these building blocks for medicinal purposes
to Re based moieties in general and [CpRe]2+ in particular.
The [Cp*Re]2+ moiety is apparently similar to the above-
Introduction
The recent years have experienced an increase in research
in medicinal inorganic chemistry mainly due to the advent
of metal complexes for replacing or complementing cispla-
tin in cancer therapy. Ru complexes, in particular those con-
taining the [Ru(arene)]2+ moiety or RuIII-imidazole-based
compounds are excellent candidates.[1,2] These complexes
have in common that one or two of the ligands can, for
instance, be replaced by N7 of guanine in DNA.[3,4] We
found that the fac-[Re(CO)3]+ core was also capable of co-
ordinating to two guanine bases in cis orientation.[5] We
have demonstrated that the guanine ligands did assume
both, a HH and a HT conformation around the metal cen-
tre. The fac-[Re(CO)3]+ moiety displays a similar reactivity
pattern with plasmid DNA as, for example, cisplatin, im-
plying a possible interaction with adjacent guanines in
DNA.[6]
Intrigued by the structural features of the [Ru(arene)]2+
or [Cp*Rh]2+ cores with three coordination sites stably
[a] Institute of Inorganic Chemistry, University of Zürich,
Winterthurerstrasse 190, 8057 Zürich, Switzerland
E-mail: ariel@aci.uzh.ch
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
Scheme 1. Summary of ReIII and 99TcIII complexes.
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F. Zobi, B. Spingler, R. Alberto
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mentioned Ru and Rh cores but its d4 electronic structure pathways of 1. Accordingly, 1 was kept in a KBr pellet at
leads to a coordination number of 7. Some synthetic investi- room temperature in the dark while another one was placed
gations with rhenium exist[7–11] but the chemistry of its in a constant stream of cold nitrogen and irradiated by light
technetium homologues is essentially unknown. In particu- from a 150-W halogen lamp. The results of these experi-
lar, the stability and reactivity in water or methanol is cru- ments are shown in Figure 1.
cial in order to assess the versatility of this core for bio-
logical purposes. Thus, as the search for novel reactive Re-
and Tc-based cores for (radio)pharmaceutical applications
is of wide interest, we have studied the chemistry of the
[Cp*MIII(CO)3Br]+ fragment (M = Re, 99Tc) in order to get
better insight in the basic reactivity and behaviour of this
core in water or methanol. An overview of the newly pre-
pared rhenium and technetium complexes is given in
Scheme 1.
Results and Discussion
Synthetic Aspects
Reaction of [Cp*M(CO)3] (M = Re, 99Tc) in toluene with
Br2 resulted in the immediate precipitation of yellow
[Cp*ReBr(CO)3]Br (1) or [Cp*99TcBr(CO)3]Br (1a) in al-
most quantitative yield. This approach is synthetically very
convenient since the same reaction in homogeneous solu-
tion results in low yield due to the formation of [(CO)3M-
(µ-Br)3M(CO)3]–.[12] Correspondingly, the complexes
[Cp*MBr(CO)3][(CO)3M(µ-Br)3M(CO)3] (for M = Re 2; for
M = 99Tc 2a) were isolated but not the equivalent Br– salts
(see below). As will become clear later, the formation of the
MI counterion [(CO)3M(µ-Br)3M(CO)3]–, which reduces the
yield to maximum of 30%, is due to parallel redox processes
taking place in solution with 1 and 1a. It was previously
suggested that excess Br2 might react with the Cp* ligand
thereby decreasing the overall yield.[12] We found no differ-
ence in the overall yield with excess of Br2, most likely due
to the immediate precipitation of 1 and 1a from toluene.
The halide counterion could be exchanged via ion metathe-
Figure 1. Re–CO IR region (1800–2250 cm–1) showing thermal re-
activity in the dark (top) and photo reactivity in the cold (bottom)
of 1. In both cases the solid line indicates the initial spectrum and
the dashed line the final spectrum.
sis with AgSbF6 and the yellow [Cp*ReBr(CO)3][SbF6] (3)
complex was obtained in good yield from 1. Further anion
exchange can be performed with e.g. [NO3]– or [ClO4]– but
[SbF6]– gave the best results.
In the solid state and as isolated from the synthesis, 1a
changes its colour from yellow to blue at room temperature
The IR spectrum of pure 1 shows three distinct CO
and under N2 within minutes. Complex 1 is relatively more stretching frequencies at 2109, 2053 and 2041 cm–1. After
stable in the solid state and a similar change is observed 24 h in the dark, three new peaks were observed at 1992,
within a 2 days period only. During this time, the colour of 1860 and 1852 cm–1. The pattern and the position of these
solid or dissolved 1 changes from yellow to orange to dark new frequencies points to a typical ReI(CO)3 spectrum of
brown. However, when kept in the dark and at –30 °C, 1 is [(CO)3Re(µ-Br)3Re(CO)3]– and are in agreement with those
stable for weeks. Analysis of the solid compounds after a reported for [NEt4][(CO)3Re(µ-Br)3Re(CO)3].[12] It was pos-
couple of days indicates the formation of an [MI(CO)3] spe- sible to confirm the authenticity of the complexes formed
cies and recrystallization gives [Cp*MBr(CO)3][(CO)3M(µ- in the dark at room temperature by X-ray structure analysis.
Br)3M(CO)3] (2: M = Re; 2a: M = 99Tc) complex.
An ORTEP presentation of cations of complexes 2 and 2a
In order to confirm the authenticity of the products after together with relevant bond lengths is given in Figure 2.
solid state decomposition, we examined the CO stretching The structures are discussed in more details later in this
frequencies by IR spectroscopy of 1 in a KBr matrix over text.
a period of 24 h. The high CO stretching frequency of 1 at
If the sample was subjected to light in the cold, the origi-
2109 cm–1 indicates a reactive carbonyl group making both, nal νCO bands of 1 disappeared almost completely and the
thermal and photolytic processes likely decomposition resulting spectrum showed two relatively broad bands at
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Potential Radiopharmaceutical Tc- and Re-Prodrugs
Figure 3. X-ray structure of the cation in cis-4. Important bond
lengths [Å] are: Re1–C1 1.922(13), Re1–C2 1.934(12), Re1–Br1
2.5821(12), Re1–Br2 2.5699(11), C1–O1 1.130(13), C2–O2
1.109(13).
Figure 2. ORTEP presentation of cations of complexes 2 (top) and
2a (bottom) (50% probability of thermal ellipsoids). Important
bond lengths [Å] are: Re1–C1 1.990(5), Re1–C2 1.962(6), Re1–Br1
2.5884(6), C1–O1 1.110(5), C2–O2 1.130(6); 99Tc1–C1 1.974(10),
99Tc1–C2 2.031(11), 99Tc1–C3 2.076(9), 99Tc1–Br1 2.5893(11), C1–
O1 1.126(11), C2–O2 1.105(11), C3–O3 1.006(10).
Scheme 2. Solid state reactions of 1.
Behaviour in Solution
2040 and 1964 cm–1 with smaller peaks at 2020, 1999 and
Complex 1 is not stable in solution and decomposes
1938 cm–1. The former major bands are assigned to the cis rapidly to give 2 via redox reactions. The fact that the same
isomer of [Cp*ReBr2(CO)2] (cis-4) in agreement with re- complex cation [Cp*ReIII(CO)3Br]+ is stable with [SbF6]– as
ported values and confirmed by an X-ray structure analy- a counterion implied an inter- and not an intramolecular
sis.[9–11]
reaction with the Br– counterion acting as a reducing agent.
Obviously, 1 is thermally unstable, yielding a partially To support this mechanism, we examined the rate of re-
reduced species whereas in the cold under light irradiation, duction of [Cp*ReIII(CO)3Br]+ as a function of the Br– con-
one coordinated CO can easily be cleaved, yielding the very centration. Given the inherent instability of 1, the redox
stable complex cis-4. Mechanistically, release of one CO stable complex 2 was used as starting material. Addition of
generates one free coordination site which is occupied by excess [Bu4N]Br to a CH2Cl2 solution of 2 initiated spectro-
the counterion Br– resulting in the formation of cis-4 as the scopic changes as shown in Figure 4 (see also Supporting
major product. Most likely, both the cis and trans isomer Information). The rate of reduction was found to be linearly
were initially formed and a concurrent solid-state photo- dependent on [Br–] concentrations. Rate constants kobs are
chemical transǞcis isomerization took place during irradi- given in Table 1. The assumption of a second-order reaction
ation. In fact, it was previously shown that visible light con- gave a rate constant of 2.48ϫ103 –1 s–1. From the observed
verted trans-[CpRe(CO)2X2] (X = Br, I) into the corre- rates we conclude that Br– reduction of 2 is the rate-de-
sponding cis-isomer in yields Ͼ80%.[13,14] Accordingly, the termining step while loss of the Cp* ligand is fast.
trans-4 isomer was not observed in this reaction but was
Obviously, compounds 1 and 1a are strong oxidation
isolated as a product from the reaction of 1 in water as agents implying that both compounds are likely to be re-
discussed below. The reaction with technetium revealed duced to lower valent species in blood serum for instance.
similar spectroscopic features but reactions were substan- From a chemical point of view, however, the facile re-
tially faster. It was possible to crystallize cis-4 and to con- duction is attractive since it might open a pathway to the
firm its structure by X-ray analysis. An ORTEP presenta- very rare class or ReII complexes by one electron reduction.
tion is given in Figure 3. Details about the structures are
discussed in the crystallography section. The solid-state re- in biology or medicine is the behaviour in water. An inter-
A further crucial aspect applying the [Cp*M]2+ moieties
actions are summarized in Scheme 2.
esting feature of the [Cp*Re(CO)3X]+ cation is a high vi-
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F. Zobi, B. Spingler, R. Alberto
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Figure 5. ORTEP of trans-4a (50% probability of thermal ellip-
soids). Important bond lengths [Å] are: 99Tc1–C1 1.982(7), 99Tc1–
C2 1.948(8), 99Tc1–Br1 2.5852(8), 99Tc1–Br2 2.5874(7), C1–O1
1.096(7), C2–O2 1.134(7).
Figure 4. Changes in UV/Vis spectra upon addition of [Br]– to a
solution of 2 in CH2Cl2, time intervals are 15 min.
In methanol instead of water, complex 3 (redox inactive
[SbF6]– as a counterion) reacts differently. The high sym-
metric CO frequency at 2110 cm–1 indicates predominant
donation from CO to Re which renders the carbon in CO
susceptible for nucleophilic attack. Accordingly, 3 reacts
rapidly with methanol to form the methyl formate complex
trans-[Cp*Re(CO)2Br(COOCH3)] (5) in 85% yield. The re-
action was followed by liquid IR analysis in different sol-
vents and in the presence of methanol. In anhydrous THF
or CH2Cl2, the IR spectrum of 3 showed νCO at 2110 and
2044 cm–1 respectively (see Supporting Information). Upon
addition of CH3OH to this solution (or in neat CH3OH),
two new bands appear at 2046 and 1976 cm–1 while the
original bands disappear completely. During the reaction,
one proton is released. Addition of bases like imidazole,
1,6-lutidine or NEt3 results in nearly quantitative formation
of 5. The structure of compound 5 could be confirmed by
X-ray structure analysis and a model based on the data is
given in Figure 6.
Table 1. [Bu4N]Br concentration (m Ϯ 0.01) dependence of the
initial rate of reduction (kobs, ms–1) of 2 (0.1 Ϯ 0.01 m solution).
[Bu4N]Br
kobsd.
0.1
0.5
1
0.030Ϯ0.006
0.102Ϯ0.011
0.246Ϯ0.017
1.201Ϯ0.036
5
bration band observed above 2100 cm–1. This weakly bound
CO should be prone to substitution by solvent molecules
or to attack by nucleophiles. In water, 1 and 1a are only
sparingly soluble but brief sonification of either complex
salt results in a yellow suspension consisting of a mixture
of cis and trans-[Cp*MBr2(CO)2] (cis/trans-4 for M = Re,
cis/trans-4a for M = 99Tc) isomers. The conversion is nearly
quantitative with isolated yields typically 45% of cis-4 and
30% of trans-4. No intermediates such as [Cp*ReB-
r(OH2)(CO)2]+ could be detected likely due to rapid anion
trapping, indicating strong Lewis acidity of the ReIII centre.
The structure of the complex trans-4a was confirmed by X-
ray structure analysis and an ORTEP presentation is given
in Figure 5. Details are discussed in the crystallography part
of this article.
The pH of the aqueous solution dropped from about 6
1
to ca. 2 and the H NMR indicated the formation of small
amounts of formic acid. TCD analysis of the head space
above the reaction mixture showed the presence of CO but
not of H2. The formation of [Cp*MIII(CO)2Br2] therefore
occurrs mainly by substitution of CO with bromide as evi-
Figure 6. Structural model of 5 based on X-ray data.
1
The H NMR spectrum (CDCl3) of 5 shows two sharp
denced by the reaction yield. To a minor extent, formation singlets at δ = 2.00 and 3.64 ppm assigned to the Cp–CH3
of a metalla-carboxylic acid such as [Cp*MIII(CO)2- groups and the O–CH3 protons, respectively. For compari-
Br(COOH)] and subsequent release of formic acid accounts son, 1H NMR and IR data of the Re and the corresponding
for the observed pH decrease. Diaz et al. suggested a 99Tc compounds are summarized in Table 2.
metalla-carboxylic acid for this reaction, liberation of CO2
In a 10% D2O/90% CD3OD solution pH* Ͼ 8, 5 did
and formation of the hydrido complex [Cp*ReIIIBrH- not show follow-up reactions. Under acidic conditions (pH*
(CO)2].[9] Protonation and substitution would then lead to Ͻ 5), however, an unusual decomposition was observed in
the products. In our reactions and with very sensitive TCD that 5 cleanly reacted to [Cp*ReI(CO)3] in about 60% iso-
analytics, we observed formic acid but no CO2 or H2.
lated yield. In order to get an insight into this unexpected
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Potential Radiopharmaceutical Tc- and Re-Prodrugs
1
Table 2. H NMR[a] (δ, ppm) and IR data [cm–1][b] data of Re and
99Tc complexes.
Complex
Cp*[a] CO
sym.[b] asym.[b]
CO
[Cp*Re(CO)3]
2.164[c] 2010
1912
2050
–
1971
1994
[Cp*Re(CO)3Br]+ (2)
2.286[d] 2110
[Cp*99Tc(CO)3Br]+ (2a)
2.254[d]
–
cis-[Cp*Re(CO)2Br2] (cis-4)
trans-[Cp*Re(CO)2Br2] (trans-4)
cis-[Cp*99Tc(CO)2Br2] (cis-4a)
trans-[Cp*99Tc(CO)2Br2] (trans-4a)
[Cp*Re(CO)2Br(COOCH3)] (5)
2.055[c] 2052
1.995[c] 2070
2.023[c] 2040[f] 1972[f]
1.898[c] 2060[f] 1985[f]
2.002[c] 2046
1974
1976
[Cp*Re(CO)2Br(COOCH2-C6H4F)] (7) 1.970[e] 2044
[a] Values referenced to residual solvent peak set at: 7.260 for
CDCl3, 1.930 for CD3CN and 3.300 for CD3OD. [b] In CH2Cl2.
[c] In CDCl3. [d] Cations of 2 and 2a in CD3CN. [e] In CD3OD.
[f] From ref.[15]
Figure 8. Time-dependent concentration of 5 during its reduction
in CD3OD (᭹), in the presence of TFA (᭿), methyl formate (᭢),
methyl formate plus TFA (᭡), formic acid (o).
Table 3. Initial rate of reduction of 5[a] to [Cp*ReI(CO)3] (kobs
,
m s–1).
redox reaction, we performed kinetic and NMR studies.
The H NMR spectrum of 5 in D2O/CD3OD 1:9 showed
1
Reaction components
kobsd.
one single Cp–CH3 signal at 1.995 ppm and the O–CH3 sig-
nal at 3.611 ppm respectively. Addition of trifluoro-acetic
acid (TFA), methyl formate or a mixture of both caused
disappearance of the original signals and appearance of a
new signal at 2.178 ppm, assigned to [Cp*ReI(CO)3]. Con-
comitantly, the resonance of free methanol at 3.336 ppm
5
0.198Ϯ0.054
0.180Ϯ0.056
0.204Ϯ0.048
0.276Ϯ0.061
2.502Ϯ0.036
5 + TFA[b]
5 + methyl formate[b]
5 + methyl formate[b] + TFA[b]
5 + formic acid[b]
[a] 2.47 m solution. [b] Under pseudo first order conditions.
1
began to grow. Figure 7 shows the typical change in the H
NMR spectrum of 5 after addition of trifluoroacetic acid
(TFA).
These data indicate that formic acid causes reduction of
5Ǟ[Cp*Re(CO)3] and serves at the same time as a source
for CO (Scheme 3). After protonation and cleavage of
methyl formate, a reactive intermediate [Cp*ReIII(CO)2-
Br(sol)]+ is formed. This intermediate could be generated
directly by abstracting a bromide from 4 with AgSbF6 in
THF. The [Cp*ReIII(CO)2Br(THF)]+ cation[16] (6) is then
allowed to react with excess unlabeled or 13C-labeled formic
Figure 7. 1H NMR spectrum of 5 (CD3OD, 0.8–4.4 ppm, left) and
the same spectrum after addition of trifluoroacetic acid (TFA)
(* indicates residual solvent peak).
Initial observed rate constants of reduction of 5 in the
presence of either TFA or methyl formate are similar within
experimental error to the rate constant observed in the ab-
sence of either reagent (Figure 8 and Table 3). A mixture of
both reagents caused a slight but significant increase in the
formation of [Cp*ReI(CO)3]. When formic acid was added
to a solution of 5, the rate of reduction increased by a fac-
tor of about 10.
Scheme 3. Summary of reactions leading to reduction of 5 to
[Cp*ReI(CO)3].
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F. Zobi, B. Spingler, R. Alberto
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acid in order to find a proof for our CO source assumption. X-ray Crystallography
IR spectra of the reaction with labelled and unlabelled for-
Crystal data and experimental details for the crystallo-
graphically characterized complexes 2, 2a, cis-4, and trans-
4a are listed in Table 4 while selected geometrical param-
eters are listed in Table 5. All compounds occur as discrete
molecules in the crystals, with no unusually short inter- or
intramolecular contacts. No crystallographically imposed
symmetry in the lattice is observed in the structure of 2a,
cis-4 and trans-4a; however, 2 possess an mirror plane run-
ning through O2C2–Re1–Br1 that bisects the Cp* ligand.
mic acid are shown in Figure 9. In THF, 6 shows two
stretching frequencies at 2044 and 1979 cm–1.[16] Reaction
with formic acid resulted in two new peaks at 2030 and
1916 cm–1 representing [Cp*ReI(CO)3]. Performing the
same reaction with isotope-enriched H13CO2H (99% 13C)
gave [Cp*ReI(CO)2(13CO)]. Correspondingly, the IR fre-
quencies of the product were red shifted by about 30 and
10 cm–1, respectively, for the symmetric and asymmetric CO
stretching modes. A summary of these reactions is given in
Scheme 3.
Table 5. Selected bond lengths and angles for compounds 2, 2a,
cis-4, and trans-4a.[a]
Compound
2
2a
cis-4
trans-4a
M–C1
M–C2
M–C3
M–Br1
1.990(5)
1.962(6)
1.990(5)[b]
2.5884(6)
1.974(10)
2.031(11)
2.076(9)
2.5893(11) 2.5821(12) 2.5852(8)
2.5699(11) 2.5874(7)
1.922(13)
1.934(12)
1.982(7)
1.948(8)
M–Br2
C1–M–C2
C1–M–C3
C2–M–C3
81.70(16)
108.8(3)[b]
81.9(4)
79.9(3)
78.7(6)
104.4(2)
81.70(16)[b] 115.2(4)
C1–M–Br1 76.26(14)
135.9(3)
77.7(5)
130.2(4)
78.21(18)
78.51(19)
C2–M–Br1 141.56(15) 75.5(2)
C3–M–Br1 76.26(14)[b] 76.4(2)
C1–M–Br2
C2–M–Br2
Br1–M–Br2
127.0(4)
78.2(4)
82.27(5)
76.13(17)
76.51(18)
138.08(3)
[a] M = transition metal ion (Re for 2 and cis-4, 99Tc for 2a and
trans-4a). [b] C3 = C1 by symmetry.
Figure 9. Solution IR spectra (anhydrous THF) of [Cp*ReIII(CO)2-
Br(THF)]SbF6 (Ϫ), [Cp*ReIII(CO)2Br(THF)]SbF6 plus HCO2H
(70%THF/30%HCO2H) (---), [Cp*ReIII(CO)2Br(THF)]SbF6 plus
H13CO2H (99% 13C, 70%THF/30% H13CO2H) (Ϫ).
The rhenium and technetium atoms are formally in the
+III oxidation state, seven-coordinate and the overall geom-
etry is that of a typical four-legged piano-stool Cp*ML4
As often observed, the [Cp*ReI(CO)3] is a thermo- complex. The M–C(CO) and C–O bonds lengths are in the
dynamic sink and is formed as the major product in dif- expected ranges of 1.95–2.15 and 1.10–1.15 Å for metal car-
ferent reactions involving the {Cp(*)Re} moiety. Thermoly- bonyl groups.[8,10,17–19] The M–Cp* (centroid) distances
sis of alkylated acylrhenate and dicarbonylrhenacyclopen- range from 1.939(9) for 2a to 1.960(7) for 2, and might be
tane complexes for example gave several organometallic viewed as almost identical and evidently insensitive to the
products with [CpRe(CO)3] being most abundant (ca. 60– differing arrangements of the carbonyl and halide basal li-
70%).[17] Cleavage of [Cp*(CO)2Re(µ-CO)Re(CO)(η2- gands in the four structures. Examination of the individual
CH3CϵCCH3)Cp*] or reaction of [Cp*(CO)2Re = Re(CO)2- M–C bond lengths to the Cp* ligand reveals, however, sys-
Cp*] with diethyl fumarate also lead to [Cp*Re(CO)3].[18]
tematic differences in structures.
Table 4. Crystallographic data for compounds 2, 2a, cis-4, and trans-4a.
Compound
2
2a
cis-4
trans-4a
Formula
FW
T [K]
C19H15Br4O9Re3
1265.55
183(2)
C19H15Br4O9Tc3
1000.95
183(2)
C12H15Br2O2Re
537.26
183(2)
C12H15Br2O2Tc
449.06
183(2)
Space group
Crystal system
Z
a [Å]
b [Å]
Pnma
orthorhombic
4
17.63762(15)
12.02664(12)
13.26823(13)
90
2814.47(5)
2.987
P21/c
monoclinic
4
10.1267(5)
16.2341(13)
17.4224(9)
90.178(6)
2864.2(3)
2.321
P21/n
monoclinic
4
6.8045(5)
26.6199(16)
8.5710(6)
108.192(8)
1474.91(17)
2.420
P21/c
monoclinic
4
8.5009(3)
12.4843(5)
13.7003(5)
102.364(3)
1420.26(9)
2.100
c [Å]
β [°]
V [Å3]
dcalcd. [Mg/m3]
R1 (wR2)[a]
0.0222 (0.0403)
0.0482 (0.1012)
1.095 and –0.672
0.0455 (0.1229)
1.896 and –1.778
0.0328 (0.0584)
0.985 and –0.674
Largest diff. peak and hole [eÅ–3] 1.362 and –2.535
[a] [IϾ2σ(I)].
4210
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Potential Radiopharmaceutical Tc- and Re-Prodrugs
The individual M–C bonds in the four structures vary, metal nonbonding d orbitals. Larger L–M–Ct-angles are
on average, from 2.21(2) to 2.40(2). With reference to the associated with stronger π-accepting ligands as a result of
projections in Figure 10, it can be seen that the long M–C a maximization of the π-interaction between the metal dz2
bonds are the ones “eclipsed” by the basal ligands with the and ligands’ π-accepting orbitals. We found that this simple
longest distance observed for the ones “eclipsed” with the π-model proposed by Poli well applies to our structures.[22]
halide. The asymmetry follows a pattern typical for CpML4 L–M–Ct angles for 2, 2a, cis-4 and trans-4a are given in
complexes and can be easily rationalized in terms of the π- Table 6 and Figure 11 defines α and α’ angles. In all struc-
acceptor properties possessed by the CO ligands.[20] The CO tures but cis-4 where α = αЈ, α (assigned to the trans-CO
ligands withdraw π-electron density from the Cp* ring at pair) is larger than α’ (assigned to the other pair of trans
the expenses of the bonds “pseudotrans” to them. The net ligands) well reflecting the greater π-accepting ability of the
effect is a lengthening of the bonds trans to the CO ligands carbonyl ligand pair.
because of the reduced π-contribution of these M–C(Cp)
Table 6. L–M–Ct angles for 2, 2a, cis-4 and trans-4a.
bonds.[20] In 2, 2a, cis-4 and trans-4a there appears to be
Complex
α [°]
αЈ [°]
also a systematic distortion from planarity for the methyl
substituents with respect to the average Cp plane. All CH3
groups are displaced from these planes in a direction away
from the rhenium atom with average deviations ranging
from 0.05(2) A to 0.26(2) Å. This type of displacement ap-
pears to be general in pentamethyl-cyclopentadienyl metal
complexes (average deviations ranging from 0.037 to
0.205 Å),[8,10,17–19] with no observable significant statistical
variation of the M–C(Cp*) bond lengths.
2
125–126
120–124
113–118
127–128
108–110
111–113
2a
cis-4
trans-4a
110–112
Complexes 2, 2a, cis-4 and trans-4a also show angular
distortion of the four “legs”. It is known that when the four
L ligands in CpML4 type of complex are not the same,
these distort from an ideal pseudo-square-pyramidal geo-
metry in a pairwise fashion.[21] Larger L–M–Ct (where Ct
denotes the centroid of the Cp ring) angles are associated
with one pair of trans ligands. This phenomenon is gen-
erally named the “angular trans influence”.[22] The distor-
Figure 11. Definition of α and αЈ angles.
The structure of complex 5 was also crystallographically
tions in the “legs” can be explained to be largely dependent determined. However, residual electron density located be-
on the π-bonding ability of the four L ligands with the two low 1 Å above the Cp* ring give a relatively large R value.
Figure 10. Individual M–C bond lengths of the Cp* ligand and methyl substituents displacement from Cp planes in structures 2, 2a, cis-
4 and trans-4a.
Eur. J. Inorg. Chem. 2008, 4205–4214
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4211

F. Zobi, B. Spingler, R. Alberto
FULL PAPER
For this reason the complex was omitted from our dis- drugs can be made. As an entry into such a strategy, we
cussion. However, a model of the molecule, derived from showed that reaction of the complexes with primary
X-ray data is given in Figure 6.
alcohols produced corresponding carboxy-carbonyl com-
plexes of the type trans-[Cp*ReIII(CO)2Br(COOR)]. These
complexes are stable under basic or neutral conditions
but in slightly acidic media they hydrolyse to
[Cp*MIII(OH2)(CO)2Br]+ which can then exert its redox ac-
tivity. Although the [Cp*ReIII(CO)3Br]+ ion cannot be used
for (radio)pharmaceutical applications as formulated, if sta-
bilized, for example, by derivatization at the cyclopen-
tadienyl ring, it could provide a scaffold for a prodrug deliv-
ery system.
Formation Alkoxycarbonyl Complexes as Prodrug Delivery
System Models
The redox instability of 1 and 1a limits the application
in biological systems. However, the rapid generation of
compounds such as 5 from 3 is intriguing since 3 could be
derivatized with other primary alcohols of interest in medic-
inal chemistry. Thus, [Cp*ReIII(CO)3Br]+ could provide a
scaffold for a prodrug delivery system. The “prodrug” con-
cept/design is a common strategy in medicinal chemistry.
Its ultimate objective is to convert an active molecule into
a clinically acceptable drug[23] as therapeutically significant
molecules may have limited utilization in clinical practice
due to poor organoleptic properties, poor aqueous solubil-
ity or other adverse effects. A successful examples of this
strategy is capecitabine, an orally available prodrug of 5-
deoxy-5-fluorouridine, which has recently come into clinical
Experimental Section
Materials: All reagents were used as received. Solvents were dis-
tilled prior to use and reactions were carried out under an inert
atmosphere. The complex [Cp*Re(CO)3] was prepared according
to a reported procedures.[26] Infrared spectra were recorded on a
Perkin–Elmer BX II spectrometer in KBr pellets or in CH2Cl2. All
1H NMR 1D spectra were recorded on a Varian 200 MHz spec-
trometer; δ values (ppm) were referenced to residual solvent peak
set at δ = 7.260 for CDCl3, 1.930 for CD3CN and 3.300 for
CD3OD.
use for the treatment of breast and colorectal cancers.[24]
A
prodrug approach focused on platinum complexes was also
recently suggested by Lippard et al.[25] Comparably, com-
plex 3 (the redox active drug) was treated with 3-fluoro- X-ray Crystallography: All crystals were grown from diffusion of
hexane in a CH2Cl2 solution of the complex. Suitable crystals were
covered with oil (Infineum V8512, formerly known as Paratone N),
mounted on top of a glass fibre and immediately transferred to the
diffractometer. Crystallographic data for structures 2a and cis-4
were measured on a Stoe IPDS diffractometer. Data were collected
at 183(2) K using graphite-monochromated Mo-Kα radiation (λ =
0.71073 Å). A total of 8000 reflections distributed over the whole
limiting sphere were selected by the program SELECT and used
for unit cell parameter refinement with the program CELL.[27] Data
were corrected for Lorenz and polarization effects as well as for
absorption (numerical). Crystals of cis-4 were non-merohedrally
twinned. Their X-ray diffraction pattern was integrated with the
help of the TWIN program.[27] The tolerance for peak overlap was
empirically optimized. The disorder of the Br and CO groups was
handled with the appropriate restrains. Crystallographic data for
structures 2 and trans-4a were collected at 183(2) K on an Oxford
Diffraction Xcalibur system with a Ruby detector (Mo-Kα radia-
tion, λ = 0.7107 Å) using graphite-monochromated radiation. The
program suite CrysAlisPro was used for data collection, semi-empir-
ical absorption correction and data reduction.[28] All structures
were solved with direct method using SHELXS-97[29] or SIR-97[30]
and were refined by full-matrix least-squares methods on F2 with
SHELXL-97.[29] The structures were checked for higher symmetry
with help of the program Platon.[31] In the structure of trans-4a a
second orientation of the complex was found in the asymmetric
unit. Since the occupancy was 4% only the heavy atoms of this
minor orientation were localized.
benzyl alcohol (3-FBA), chosen as a simple model of fluoro-
uracil. The corresponding (now redox inactive) alkoxy-
carbonyl complex [Cp*ReIII(CO)2Br(COOCH2-C6H4F)] (7)
(Scheme 4) could be isolated (analytical data of 7 were
given in Table 2. See also the Experimental Section).
Scheme 4. Formation of [Cp*ReIII(CO)2Br(COOCH2-C6H4F)] (7).
The prodrug 7 is stable for hours at neutral conditions
in water. Under slightly acidic conditions (pH = 6.11), 7
rapidly releases 3-FBA and converts to [Cp*ReI(CO)3]. Hy-
drolysis of the primary alcohol from 7 takes place at signifi-
cantly higher rate than for example 5. This opens the pos-
sibility to tune the rate of drug activation by selecting the
appropriate alcohol.
Conclusions
CCDC-680535 (for 2), -680536 (for 2a), -680537 (for cis-4),
-680538 (for trans-4a) contain the supplementary crystallographic
data. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
The complexes [Cp*MIII(CO)3Br]+ (M = Re, 99Tc) could
be synthesized in very good yield. They show different types
of reactivities which makes them useful as synthons for
2+
{Cp*ReIII
}
chemistry. Redox activity and lability of one
[Cp*ReIII(CO)3Br]Br (1): To a stirred solution of Cp*ReI(CO)3
(120 mg, 0.30 mmol) in toluene (10 mL) at 0 °C, Br2 (30 µL,
CO ligand limit the application in medicinal inorganic
chemistry at a first glance. However, if redox activity can
be “switched on” at a particular site or organ, attractive 0.59 mmol) was added causing the immediate precipitation of a
4212 Eur. J. Inorg. Chem. 2008, 4205–4214
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Potential Radiopharmaceutical Tc- and Re-Prodrugs
bright yellow solid. After 10 min stirring was halted, the product
filtered through a fritted funnel and washed with ice cold toluene
and ice cold ether. The fritted funnel was wrapped in aluminium
foil and the solid dried under vacuum for 1h. The compound was
then transferred to a round-bottom flask equipped with a side arm
which was evacuated and filled with N2 three times and then stored
C14H18BrO4Re (516.40): calcd. C 32.56, H 3.51; found C 32.81, H
3.54. 1H NMR (200 MHz, CD3OD): δ = 1.994 (s, 15 H), 3.610 ppm
(s, 3 H). IR (solid state): ν = 2029, 1970 (CϵO), 1636 (C=O) cm–1.
˜
IR (liquid CH Cl ): ν = 2045, 1974 (CϵO), 1641 (C=O) cm–1. ESI
˜
2
2
MS (+ve): m/z = 539.04 [M] + Na+.
[Cp*ReIII(CO)2Br(CO2CH2-C6H4F)] (7): To a stirred solution of
imidazole (60 mg, 0.88 mmol) and 3-fluorobenzyl alcohol (3-FBA,
114 µL, 1 mmol) in CH2Cl2 (8 mL) at room temperature, 1
(100 mg, 0.19 mmol) was added giving an orange mixture. The re-
action was warmed to 37 °C and stirred for 12h. The solvent was
then evaporated under vacuum leaving an orange oil. A small
amount of ether (5–7 mL) was added resulting in the extraction of
complex 7, imidazole and other impurities. The ether fraction was
then washed three times with an equal volume of deionized water
in order to remove imidazole (final pH of water extract: 8–9) and
dried with MgSO4. The solvent was evaporated and the resulting
orange oil was dissolved in a minimum amount of a 3% Et3N in
CH2Cl2. Silica-gel column chromatography with 3% Et3N in
CH2Cl2 as the eluent gave 7 (first eluting orange band) as a viscous
orange oil which was transferred to a round-bottom flask equipped
with a side arm dried under vacuum then evacuated and filled with
N2 three times and stored at –30 °C. After a while the oil crys-
tallizes at –30 °C. Yield 37 mg, 34%. 1H NMR (200 MHz,
CD3OD): δ = 1.970 (s, 15 H), 5.068 (s, 2 H), 7.021–7.202 (m, 3 H),
1
at –30 °C. Yield 146 mg, 87%. H NMR (200 MHz, CD3CN): δ =
2.286 (s, 15 H) ppm. IR (solid state): ν = 2109, 2053, 2041 (CϵO)
˜
cm–1. IR (liquid CH Cl ): ν = 2108, 2057, 2049 (CϵO) cm–1.
˜
2
2
[Cp*TcIII(CO)3Br]Br (1a): The same procedure used to synthesize
1 was employed in this case using Cp*TcI(CO)3 (30 mg scale). Yield
38 mg, 85%. The complex is unstable and decomposes within min-
1
utes from its isolation. H NMR (200 MHz, CD3CN): 2.254 (s, 15
H).
[Cp*ReIII(CO)3Br]SbF6 (3): To a stirred solution of AgSbF6
(61 mg, 0.18 mmol) in methanol 1 (100 mg, 0.18 mmol) was added
causing the immediate precipitation of AgBr. After 5 min stirring
was halted, AgBr filtered and the solvent evaporated to dryness.
The residue was dissolved in a minimum amount of CH2Cl2 and
hexane was added resulting in the precipitation of a yellow powder.
This product was filtered through a fritted funnel and washed with
ice-cold diethyl ether. The fritted funnel was wrapped in aluminium
foil and the solid dried under vacuum for 1h. The compound was
then transferred to a round-bottom flask equipped with a side arm
which was evacuated and filled with N2 three times and then stored
at –30 °C. Yield 50 mg, 39%. C13H15BrF6O3ReSb (721.12): calcd.
C 21.65, H 2.10; found C 22.88, H 2.51. 1H NMR (200 MHz,
7.370 ppm (s, 1 H). IR (liquid CH Cl ): ν = 2044, 1976 (CϵO),
˜
2
2
1655 (C=O) cm–1. ESI MS (+ve): m/z 633.09 [M] + Na+.
Supporting Information (see also the footnote on the first page of
this article): UV/Vis and IR spectra.
CD CN): δ = 2.286 ppm (s, 15 H). IR (solid state): ν = 2109, 2053,
˜
3
2041 (CϵO) cm–1. IR (liquid CH Cl ): ν = 2108, 2057, 2049 (CϵO)
˜
2
2
cm–1.
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cis/trans-[Cp*ReIII(CO)2Br2] (cis/trans-4): Complex
1 (100 mg,
0.18 mmol) was suspended in water and then sonicated for 30 min
at room temp. The resulting brown precipitate containing both iso-
mers of [Cp*ReIII(CO)2Br2] was extracted with CH2Cl2 and dried
with MgSO4. This mixture was chromatographed on a silica gel
column prepared in dichloromethane. Successive elution with
dichloromethane gave first trans-[Cp*ReIII(CO)2Br2] (29 mg, 31%
yield) from a red band, and finally cis-[Cp*ReIII(CO)2Br2] (43 mg,
45% yield) from a brown band. Each [Cp*ReIII(CO)2Br2] isomer
was recrystallized from mixtures of dichloromethane and hexane.
C12H15Br2O2Re (537.26): calcd. C 26.83, H 2.81; (cis) found C
26.91, H 2.74. (trans) C 26.41; H 2.39%. 1H NMR (200 MHz,
CDCl3): (cis) δ = 2.055 (s, 15 H), (trans) 1.955 ppm (s, 15 H). IR
(solid state): (cis) ν = 2017, 1936 (CϵO), (trans) 2042, 1970 (CϵO),
˜
1636 (C=O) cm–1. IR (liquid CH Cl ): (cis) ν = 2033, 1958 (CϵO),
˜
2
2
(trans) (CϵO), 2050, 1981 (C=O) cm–1.
cis/trans-[Cp*TcIII(CO)2Br2] (cis/trans-4a): Complexes cis/trans-4a
were obtained as described for cis/trans-4. Yields for trans-[Cp*-
TcIII(CO)2Br2] and cis-[Cp*TcIII(CO)2Br2] were comparable to the
1
Re analogues. H NMR (200 MHz, CDCl3): (cis) δ = 2.023 (s, 15
H), (trans) 1.898 ppm (s, 15 H). IR (liquid CH Cl ): ν = (cis) 2040,
˜
2
2
1972 (CϵO); (trans) (CϵO), 2060, 1985 (C=O) cm–1.
[Cp*ReIII(CO)2Br(CO2CH3)] (5): To a stirred solution of imidazole
(30 mg, 0.44 mmol) in methanol (4 mL) at room temperature, 1
(50 mg, 0.09 mmol) was added giving an orange mixture. The reac-
tion was warmed to 37 °C and stirred for 12 h. The solvent was
then evaporated under vacuum leaving a light orange solid. A small
amount of diethyl ether (2–3 mL) was added resulting in the extrac-
tion of complex 5. Evaporation of the solvent gave 5 as bright
orange needles. These were transferred to a round-bottom flask
equipped with a side arm which was evacuated and filled with N2
three times and then stored at –30 °C. Yield 39 mg, 85%.
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4213

F. Zobi, B. Spingler, R. Alberto
FULL PAPER
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Received: March 11, 2008
Published Online: May 8, 2008
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