Ethylenediamine- and propylenediaminediacetic acid derivatives as ligands for the "fac-[M(CO)3]+" core (M = Re, 99mTc)

Article abstract of DOI:10.1016/j.ica.2006.02.023

The reaction of Re(CO)₅Cl with o- or p-N-(nitrophenyl)ethylenediaminediacetic acid (H₂L¹, H₂L²) and o- or p-N-(nitrophenyl)propylenediaminediacetic acid (H₂L³, H₂L

Full text of DOI:10.1016/j.ica.2006.02.023

Inorganica Chimica Acta 359 (2006) 2128–2134
www.elsevier.com/locate/ica
Ethylenediamine- and propylenediaminediacetic acid derivatives
as ligands for the ‘‘fac-[M(CO)3]+’’ core (M = Re, 99mTc)
a,c
a
a
d
´
Mustapha Allali , Sandra Cousinie , Marie Gressier , Christian Tessier ,
d
b
a
a,
*
`
´
Andre L. Beauchamp , Yvon Coulais , Michele Dartiguenave , Eric Benoist
a
Laboratoire de Chimie Inorganique, Universite´ Paul Sabatier, Batiment IIR1, porte 180, 118, route de Narbonne, 31062 Toulouse, France
Laboratoire ‘‘Traceurs et traitement de l’image’’, Faculte´ de Me´decine de Purpan, EA 3033, 133, route de Narbonne, 31062 Toulouse, France
b
c
Laboratoire de Chimie Organique et d’Agrochimie, Universite´ Ibn Tofail, Faculte´ des Sciences, Ke´nitra, Morocco
De´partement de Chimie, Universite´ de Montre´al, CP 6128, Succ. Centre-ville, Montre´al, QC H3C 3J7, Canada
d
Received 19 October 2005; accepted 13 February 2006
Available online 6 March 2006
Abstract
The reaction of Re(CO)5Cl with o- or p-N-(nitrophenyl)ethylenediaminediacetic acid (H2L1, H2L2) and o- or p-N-(nitrophenyl)prop-
ylenediaminediacetic acid (H2L3, H2L4) in methanol leads to the formation of stable anionic [Et3NH][Re(CO)3(L)] Æ H2O complexes 1–4.
These compounds have been characterized by means of IR, mass spectrometry, elemental analysis, NMR and conductimetry, as well as
X-ray crystallography for 2 and 3. The [Re(CO)3]+ moiety is coordinated via the nitrogen of the iminodiacetic acid unit and two oxygens
of monodentate carboxylate groups. In each case, the nitro group of the aromatic ring remains uncoordinated. The analogous techne-
tium-99m complexes 10 and 30 were also prepared quantitatively by the reaction of H2L1 and H2L3, respectively, with the fac-
[
99mTc(CO)3(H2O)3]+ precursor in ethanol. The corresponding Re and 99mTc compounds were shown to possess the same structure
by means of HPLC studies. The high affinity of these ligands for the Tc(I) or Re(I) core, coupled with the easiness of their derivatization
(by reduction of the nitro group in amino group), implies that the utilization of this ligand system to develop target-specific radiophar-
maceuticals for diagnosis and therapy is promising.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: Tricarbonylrhenium(I) complexes; Technetium-99m; Organometallic; Crystal structures
1. Introduction
ter, conjugated with the easy production of the fac-
99mTc(CO)3(H2O)3]+ precursor (which is now commercially
[
The development of novel radiopharmaceuticals in
nuclear medicine based on the 99mTc(CO)3 complexes has
attracted growing attention since Alberto and coll. devel-
oped a convenient low-pressure synthesis for the preparation
of 99mTc-tricarbonyl complexes from the pertechnetate ion
available as IsoLink kitꢁ from Malinckrodt), could explain
this interest. Moreover, the analogous fac-[188Re(CO)3
(H2O)3]+ core has been developed recently, rhenium-188
being a promising bꢀ radionuclide for therapeutic applica-
tions [2].
Although different new ligand systems have been devel-
oped [3–8], recent in vivo and in vitro investigations on
the stability of a variety of complexes containing the
[M(CO)3]+ core (M = 99mTc, 188Re) showed that tridentate
chelating systems are preferable, since they form organome-
tallic compounds with more favourable pharmacokinetics
[2,9]. A Tc- or Re-tricarbonyl complex with a tridentate
ligand is less prone to undergo undesired reactions like
ꢀ
TcO4 [1]. The kinetic inertness and chemical robustness of
complexes with this core, the high affinity of the Tc(I) ion
for a large variety of donor atoms, the organometallic nature
of this core which renders chelation more covalent in charac-
*
Corresponding author. Fax: +33 561 556 118.
E-mail address: benoist@chimie.ups-tlse.fr (E. Benoist).
0020-1693/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2006.02.023

M. Allali et al. / Inorganica Chimica Acta 359 (2006) 2128–2134
2129
ments, the protons (or carbons) were numbered from 1 to
6 starting from carbon bearing the aromatic amine nitro-
gen and turning clockwise. Infrared spectra were recorded
as KBr pellets with a Bruker Vector 22 spectrometer in the
range 4000–400 cmꢀ1. Negative electrospray mass spectra
were obtained on a NERMAG R 10–10 mass spectrome-
ter. Carbon, hydrogen and nitrogen analyses were carried
out by the microanalytical department of the Ecole Natio-
.HCl
N
H
N
COOH
n
COOH
O2N
o-NO2, n = 1: H2L1 ; p-NO2, n = 1: H2L2
o-NO2, n = 2: H2L3 ; p-NO2, n = 2: H2L4
Scheme 1. NO2Ph-EDDA and NO2Ph-PDDA ligands.
´
nale Superieure de Chimie de Toulouse. HPLC analyses,
purifications and comparisons were achieved on a Waters
600E gradient chromatograph with a Waters Lambda
Max UV detector, a SAIP radioactivity detector and an
ICS dual integrator for effluent monitoring, and a Mache-
rey-Nagel C-18 reversed phase column (10 lm, 125
· 4.6 mm) using MeOH/sodium carbonate buffer 0.1 M
pH 8.0 (60/40 v/v) as eluent (flow rate of 1 mL/min). The
effluent from the column was monitored by UV absorbance
at 220 nm for Re or c-ray detection for the 99mTc
complexes.
cross-metalation, due to its coordinative saturation and
because thermodynamic factors strongly disfavour the dis-
sociation of a donor atom from the tridentate ligand.
Among these ligands, those based on amino polycarboxylic
acid systems like iminodiacetic acid (IDA) react readily with
the fac-[M(CO)3]+ core to form complexes with a stable
octahedral coordination sphere, where substitution reaction
via a dissociative or an associative mechanism is unlikely
[10].
In this regard, as part of our activities on the synthesis
of new substitution-inert technetium(I) and rhenium(I)
compounds, we recently developed a new range of N-
substituted iminodiacetic acid derivatives [11]. They
comprise an IDA unit for tridentate coordination to the
fac-[M(CO)3]+ moiety (M = Re, 99mTc), an aromatic ring
system bearing a nitro group as linking site model, and a
tethering moiety (ethylene or propylene bridge) between
the linking and coordinating sites. Co-ordination of N-
(nitrophenyl)ethylenediaminediacetic acid NO2Ph-EDDA
(H2L1, H2L2) and N-(nitrophenyl)propylenediaminediace-
tic acid NO2Ph-PDDA (H2L3, H2L4) ligands (see Scheme
1) to the usual rhenium precursor Re(CO)5Cl gave
straightforwardly complexes of the general formula
[Et3NH][Re(CO)3(L)] Æ H2O under mild conditions. In
the present work, we are reporting the synthesis and the
physico-chemical characterization of these four novel tri-
carbonylrhenium(I) complexes, together with X-ray crys-
tal structures of two representative examples. The
reactivity of these ligands with the fac-[99mTc(CO)3-
(H2O)3]+ precursor was also investigated. The correspond-
ing Re and 99mTc compounds were shown to have the
same structure by a comparative HPLC study.
2.2. Synthesis of complexes
The synthetic procedure was very similar for the prepa-
ration of the rhenium(I) complexes 1–4. They were pre-
pared by a substitution route from commercial Re(CO)5Cl.
General method. 0.3 mmol of the ligand, 250 mg
(0.3 mmol) of commercial Re(CO)5Cl and 1.26 ml
(0.9 mmol) of Et3N were dissolved in MeOH and stirred
at 60 ꢂC for 4 h. After cooling to room temperature, the
yellow solution was evaporated to dryness. The crude
was washed with ether (3 · 30 mL), then the residue was
purified by column chromatography on silica gel (eluent
CH2Cl2/MeOH: 8/2) to give the complex as the triethyl-
ammonium salt.
2.2.1. [Et3NH][Re(CO)3(L1)] Æ H2O (1)
100 mg of H2L1 led to 188 mg of 1 as a yellow powder
(Yield 92%).
1H NMR (300 MHz, DMSO-d6) dH (ppm): 1.07 (t, 9H,
J = 7.1 Hz, 3CH3); 3.01 (q, 6H, J = 7.1 Hz, 3NCH2); 3.39
(m, 2H, NArCH2); 3.48 (AB pattern, 2H, J = 16.0 Hz,
CH2CO); 3.59 (m, 2H, NCH2); 3.65 (AB pattern, 2H,
J = 16.0 Hz, CH2CO); 6.63 (m, 1H, H-6); 7.17 (d, 1H,
J = 8.5 Hz, H-4); 7.50 (m, 1H, H-5); 8.00 (dd, 1H,
J = 8.5 and 1.5 Hz, H-3); 8.13 (t, J = 6.0 Hz, 1H, NH).
13C NMR (75.5 MHz, DMSO-d6) dC (ppm): 9.17 (3CH3);
38.5 (3CH2); 46.2 (NCH2); 63.2 (2CH2CO); 67.2 (NCH2);
114.9 (C-6); 116.0 (C-4); 126.8 (C-3); 131.8 (C-2); 137.2
(C-5); 145.0 (C-1); 178.9 (2CO2); 199.1, 199.4 (3CO). IR
2. Experimental
2.1. General methods
All reagents and organic solvents used in this study were
reagent grade and used without further purification. N-
(nitrophenyl)ethylenediaminediacetic acid (H2L1, H2L2)
and N-(nitrophenyl)propylenediaminediacetic acid (H2L3,
H2L4) derivatives were prepared as described previously
[11]. Re(CO)5Cl was purchased from Aldrich Chem. Co.
1H and 13C NMR spectra were recorded on a Bruker AC
300. Chemical shifts are indicated in d values (ppm) down-
field from internal TMS. For aromatic ring NMR assign-
(KBr/cmꢀ1):
mN–H = 3370; mC@O (COORe) = 1667,
m(CO) = 1872, 1908, 2013. MS (ESꢀ): 564 (60), 566 (100)
[Mꢀ]. Anal. Calc. for C21H31N4O10Re: C, 36.8; H, 4.6; N,
8.2. Found: C, 37.3; H, 4.4; N, 8.4%.
2.2.2. [Et3NH][Re(CO)3(L2)] Æ H2O (2)
100 mg of H2L2 led to 180 mg of 2 as yellow crystals
(Yield 88%).

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M. Allali et al. / Inorganica Chimica Acta 359 (2006) 2128–2134
1H NMR (300 MHz, DMSO-d6) dH (ppm): 1.18 (t, 9H,
added successively 200 lL of an aqueous acetic acid/
sodium carbonate buffer 0.1 M pH 3.4 and 40 mL of a
freshly prepared [99mTc(CO)3(H2O)3]+ solution. The vial
was sealed with a Teflon-lined cap and the mixture was
heated at 80 ꢂC for 30 min. After cooling, the resulting
complex was analyzed and purified with the HPLC system
described above.
J = 7.3 Hz, 3CH3); 3.08 (q, 6H, J = 7.3 Hz, 3NCH2); 3.40
(m, 2H, NArCH2); 3.45 (m, 2H, NCH2); 3.52 (AB pattern,
2H, J = 15.6 Hz, CH2CO); 3.64 (AB pattern, 2H,
J = 15.6 Hz, CH2CO); 6.74 (d, 2H, J = 9.3 Hz, H-2 and
H-6); 7.28 (t, 1H, J = 6.0 Hz, NH); 8.08 (d, 2H,
J = 9.4 Hz, H-3 and H-5). 13C NMR (75.5 MHz, DMSO-
d6) dC (ppm): 9.3 (3CH3); 39.2 (3CH2); 46.3 (NCH2); 63.6
(2CH2CO); 67.5 (NCH2); 110.0 (C-2 and C-6); 126.9 (C-3
and C-5); 136.8 (C-4); 154.7 (C-1); 179.0 (2CO2); 199.2,
2.4. X-ray crystal structure determination of complexes 2
and 3
199.6 (3CO). IR (KBr/cmꢀ1):
mN–H = 3388; mC@O
(COORe) = 1641; m(CO) = 1881, 1918, 2024. MS (ESꢀ):
564 (60), 566 (100) [Mꢀ]. Anal. Calc. for C21H31N4O10Re:
C, 36.8; H, 4.6; N, 8.2. Found: C, 36.5; H, 4.6; N, 8.0%.
[Et3NH][Re(CO)3(L2)] Æ H2O (2) and [Et3NH][Re(CO)3
(L3)] Æ H2O (3) were crystallized by slow evaporation of a
methanol solution. The data were collected on a Bruker
P4 diffractometer using graphite-monochromated Mo Ka
2.2.3. [Et3NH][Re(CO)3(L3)] Æ H2O (3)
radiation (k = 0.71073 A). Automatic search in the recipro-
˚
105 mg of H2L3 led to 184 mg of 3 as orange crystals
(Yield 88%).
cal sphere yielded the reduced cell. The Niggli parameters
indicated monoclinic unit cells, primitive for 2 and C-cen-
tred for 3. A whole sphere of data was collected, which were
corrected for the Lorentz effect, polarization and absorption
(psi-scan). These data confirmed the 2/m Laue symmetry
and they were averaged to provide the basic two-octant
set. Space group P21/n was uniquely defined for 2 from
the systematic absences (h0l, h + l ¼ 2n; 0k0, k ¼ 2n). For
3, space groups Cc and C2/c were consistent with the sys-
tematic absences (hkl, h + k ¼ 2n; h0l, l ¼ 2n). The structure
solved and refined normally in the centric C2/c group.
All calculations were done with the SHELXTL-97 package
[12]. The structures were solved by direct methods with
SHELXS-97 [13] and refined on F 2o using all reflections with
SHELXL-97 [14]. The coordinates of the Re atom were
obtained first, and the remaining non-hydrogen atoms were
located from DF maps. These atoms were refined aniso-
tropically by full-matrix least squares. The hydrogen
atoms were generally placed at idealized positions (N–
1H NMR (300 MHz, DMSO-d6) dH (ppm): 1.18 (t, 9H,
J = 7.2 Hz, 3CH3); 1.98 (m, 2H, CH2); 3.08 (q, 6H,
J = 7.2 Hz, 3NCH2); 3.32 (m, 4H, NArCH2 + NCH2);
3.41 (AB pattern, 2H, J = 16.0 Hz, CH2CO); 3.51 (AB pat-
tern, 2H, J = 16.0 Hz, CH2CO); 6.68 (m, 1H, H-6); 7.17 (d,
1H, J = 8.7 Hz, H-4); 7.54 (m, 1H, H-5); 8.05 (d, 1H,
J = 8.7, H-3); 8.15 (m, 1H, NH). 13C NMR (75.5 MHz,
DMSO-d6) dC (ppm): 9.1 (3CH3); 24.4 (CH2); 39.4
(3CH2); 46.2 (NCH2); 63.3 (2CH2CO); 67.2 (NCH2);
115.1 (C-6); 115.2 (C-4); 126.7 (C-3); 131.5 (C-2); 137.1
(C-5); 145.5 (C-1); 178.8 (2CO2); 199.3, 199.5 (3CO). IR
(KBr/cmꢀ1):
mN–H = 3370; mC@O (COORe) = 1637;
m(CO) = 1879, 1917, 2019. MS (ESꢀ): 578 (60), 580 (100)
[Mꢀ]. Anal. Calc. for C22H33N4O10Re: C, 37.8; H, 4.8; N,
8.0. Found: C, 38.0; H, 4.3; N, 7.9%.
2.2.4. [Et3NH][Re(CO)3(L4)] Æ H2O (4)
105 mg of H2L4 led to 194 mg of 4 as yellow crystals
(Yield 93%).
H = 0.86 A; C–H = 0.97 A) and allowed to ride on the
supporting atom. They were assigned fixed isotropic dis-
placement parameters Uiso = 1.2 · Ueq of the atom to
which they were bonded (1.5 · Ueq for methyl groups).
The hydrogen atoms of the water molecule were refined,
but they were constrained to have equal O–H distances
and equal displacement parameters. In both structures,
the [Et3NH]+ cation was disordered over two orientations
and constraints on the distances and angles were applied
during the refinement. Occupancy factors for the two
groups were refined in the first place, then rounded off to
0.50/0.50 for 3 and 0.80/0.20 for 2, and finally fixed for
the rest of the refinement. The relevant crystal data are
summarized in Table 1.
˚
˚
1H NMR (300 MHz, DMSO-d6) dH (ppm): 1.15 (t, 9H,
J = 7.2 Hz, 3CH3); 1.90 (m, 2H, CH2); 3.13 (q, 6H,
J = 7.2 Hz, 3NCH2); 3.20 (m, 2H, NArCH2); 3.31 (m, 2H,
NCH2); 3.35 (AB pattern, 2H, J = 15.9 Hz, CH2CO);
3.52 (AB pattern, 2H, J = 15.9 Hz, CH2CO); 6.67 (d,
J = 9 Hz, 2H, H-2 and H-6); 7.32 (m, 1H, NH); 7.98 (d,
2H, J = 9 Hz, H-3 and H-5). 13C NMR (75.5 MHz,
DMSO-d6) dC (ppm): 9.2 (3CH3); 24.1 (CH2); 40.2
(3CH2); 46.3 (NCH2); 63.3 (CH2CO); 67.4 (NCH2); 111.2
(C-2 and C-6); 126.7 (C-3 and C-5); 136.2 (C-4); 155.0
(C-1); 178.7 (2CO2), 199.3, 199.5 (3CO). IR (KBr/cmꢀ1):
m
N–H = 3316; mC@O (COORe) = 1651; m(CO) = 1878,
1915, 2024; MS (ESꢀ): 578 (60), 580 (100) [Mꢀ]. Anal. Calc.
for C22H33N4O10Re: C, 37.8; H, 4.8; N, 8.0. Found: C,
38.2; H, 4.4; N, 8.0%.
3. Results and discussion
3.1. Ligand syntheses
2.3. Radiolabelling of H2L1 and H2L3
The four ligands (o-; p-NO2Ph-EDDA and o-; p-NO2Ph-
PDDA) (see Scheme 1) used as chelating agents in the pres-
ent work were synthesized in good yield via multistep reac-
To a solution of the chelator H2L1 or H2L3 (10ꢀ3 M in
ethanol, 200 lL) in a 10 mL glass vial under nitrogen, were

M. Allali et al. / Inorganica Chimica Acta 359 (2006) 2128–2134
2131
H2L1 to H2L4 and Re(CO)5Cl in methanol in the presence
of triethylamine as deprotonating agent (see Scheme 2).
Co-ordination took place in 4 h under reflux and led for
each ligand, after purification by column chromatography,
to a single tricarbonylrhenium complex isolated as a trie-
thylammonium salt of general formula [Et3NH][Re(CO)3-
(L)] Æ H2O, as evidenced from the elemental analyses. All
complexes exhibited a good solubility in polar solvents
and in water/alcohol mixtures, which was a prerequisite
for biological studies. The low-spin d6 nature of the metal
centre renders the complexes very robust and no decompo-
sition was observed in the solid state as well as in organic
polar solvents for a period of weeks, as shown by HPLC
and NMR.
The four tricarbonylrhenium complexes were character-
ized by the usual analytical techniques, including X-ray dif-
fraction analysis for complexes 2 and 3. The facial
arrangement of the carbonyl groups in all complexes is evi-
denced from the CO-stretching absorptions in the IR spec-
tra. The three strong m(CO) stretching bands appear in the
region of 2025–1880 cmꢀ1 (see Table 2), indicating the
presence of the fac-[Re(CO)3]+ core [15]. In addition, a sin-
gle, strong absorption of the carboxylate functionalities
with a significant blue shift due to metal coordination
could be observed at ca. 1650 cmꢀ1 in the four complexes.
Tridentate coordination of the IDA ligand to the metal
core was confirmed by the NMR experiments.
The resonances were assigned on the basis of 1D
(1H/13C) as well as 2D (1H–1H COSY and 1H–13C HMQC)
NMR experiments. For the free ligands H2L1–H2L4, the
signals of the NCH2COO protons of the IDA moiety are
singlets in the 3.51–3.59 ppm range [11]. After the ligands
have been coordinated to rhenium, these proton signals
split into two doublets corresponding to an AB-spin system
in the region 3.35–3.52 and 3.52–3.65 ppm with coupling
constants consistent with geminal coupling (15.6–16.0 Hz)
(see Table 2). The coordination to the metal centre results
in a rigid environment which produces non-equivalence of
the protons in the methylene groups close to the rhenium
site. These results are in accordance with the proposed
Table 1
Crystal data for [Et3NH][Re(CO)3(L2)] Æ H2O (2) and [Et3NH][Re-
(CO)3(L3)] H2O (3)
Complex 2
Complex 3
Formula
M
C21H31N4O10Re
685.70
C22H33N4O10Re
699.72
Crystal system
Color/shape
Crystal size (mm3)
Space group
monoclinic
yellow/block
0.50 · 0.46 · 0.30
P21/n
monoclinic
yellow/platelet
0.52 · 0.46 · 0.16
C2/c
˚
a (A)
7.7210(10)
11.315(2)
29.643(4)
90
31.117(6)
11.648(2)
16.335(3)
90
˚
b (A)
˚
c (A)
a (ꢂ)
b (ꢂ)
c (ꢂ)
91.240(10)
90
113.65(2)
90
3
˚
V (A )
2589.1(7)
4
5423(2)
8
Z
T (K)
d (g/cm3)
F(000)
Total reflections
Independent reflections
Observed reflections [I > 2r(I)]
Data/restraints/parameters
Final R indices [I > 2r(I)]a
293(2)
293(2)
1.759
1.714
1360
2784
19793
22085
5087
5333
4391
4276
5087/71/372
R1 = 0.0270,
wR2 = 0.0626
R1 = 0.0350,
wR2 = 0.0661
5333/20/383
R1 = 0.0312,
wR2 = 0.0639
R1 = 0.0469,
wR2 = 0.0690
R indices (all data)a
Sa
1.118
1.050
P
P
P
P
2
2 1=2
a
R1 = iFo| ꢀ |Fci/ |Fo|,
wR2 ¼ f ½wðF 2o ꢀ F c2Þ ꢁ= wðF 2oÞ g
,
P
2
1=2
S ¼ f ½wðF 2o ꢀ F 2c Þ ꢁ=ðNobs ꢀ NparamÞg
.
tions as previously described [11]. The coordinating imino-
diacetic acid unit acts as a tridentate dianionic ligand by
coordination via the two negatively charged monodentate
carboxylate functions and the tertiary nitrogen bearing
these two carboxylate groups.
3.2. Syntheses and characterization of the rhenium/
technetium complexes
The rhenium complexes 1–4 were prepared in excellent
yields (88–93%) by reacting equivalent amounts of ligands
NO2
NH
n
Hax
Hax
Heq
Heq
Cl
N
H2L1-4, Et3N, MeOH, 60o
OC
OC
CO
CO
OC
O
CO
Re
Re
CO
O
O
88-93%
O
CO
Scheme 2.

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M. Allali et al. / Inorganica Chimica Acta 359 (2006) 2128–2134
Table 2
Selected 1H, 13C NMR and IR data of rhenium(I) complexes 1–4
NMR
IR
CH2CO dH Heq/Hax (ppm);JH–H (Hz)
COO/CO dC (ppm)
Re(CO)3 m (cmꢀ1
)
Complex 1
Complex 2
Complex 3
Complex 4
3.48/3.65; J = 16.0
3.52/3.64; J = 15.6
3.41/3.51; J = 16.0
3.35/3.52; J = 15.9
178.9/199.1; 199.4
179.0/199.2; 199.6
178.8/193.3; 199.5
178.7/193.3; 199.5
1872; 1908; 2013
1881; 1918; 2024
1879; 1917; 2019
1878; 1918; 2024
tridentate coordination via the tertiary amine and the two
carboxylate groups. Moreover, in each complex, the hydro-
gen resonances of the nitrophenyl moiety were either
unchanged or exhibited very minor shifts compared to
those of the free ligand. The lack of appreciable shifts con-
firms the pendant nature of the nitrophenyl ring. There-
fore, coordination or interaction of the metal centre with
the nitro group (linking site model) can largely be excluded.
The 13C NMR spectra show only two peaks near 199–
200 ppm for the three CO ligands of the fac-[Re(CO)3]+
moiety (see Table 2). The characteristic 2:1 peak height
ratio for these carbonyl resonances indicates that two CO
groups are magnetically equivalent. This result implies that
the coordination sphere exhibits mirror symmetry includ-
ing one of the three facial carbonyl groups and the coordi-
nated amino group, as confirmed by the X-ray structures of
complexes 2 and 3. The same spectroscopic feature has
been recently reported for rhenium-tricarbonyl complexes
of IDA derivatives [16] or SAAC (Single Amino ACid)
ligands [6]. Similarly, the carbon atoms of the two carbox-
ylate groups are magnetically equivalent and downfield
shifted by 6–7 ppm upon co-ordination. All these NMR
results indicate that the coordination sphere of complexes
1–4 retains its solid-state structure in solution.
Fig. 1. ORTEP drawing of the [Re(CO)3(L2)]ꢀ complex anion (2) with
numbering scheme. Thermal ellipsoids are drawn at 30% probability level.
Negative-ion ESI-MS spectra of each Re-complex
showed the parent peak with the correct isotope distribution
pattern consistent with the monomeric anion
[Re(CO)3(L)]ꢀ, without significant fragmentation. The con-
ductivity of 105–115 Xꢀ1 cm2 molꢀ1 for all complexes in
methanol corresponds to a 1:1 electrolyte [17], as expected.
3.3. Crystallographic studies
The X-ray diffraction analyses confirm that the metal
centre is in a distorted octahedral environment. ORTEP
views of the anionic units of complexes 2 and 3 are shown
in Figs. 1 and 2, respectively. Selected bond distances and
angles are given in Table 3.
Both complexes crystallize as triethylammonium salt
and contain one lattice water molecule. In the monomeric
complex anion, the three CO ligands are coordinated to
one face of the octahedron, whereas the other face is occu-
pied by a tridentate IDA dianion, bonded via two carbox-
ylate oxygens and the adjacent tertiary amino group,
forming two five-membered chelate rings. As suggested
by the spectroscopic data, the environment of the metal
exhibits in both cases an approximate mirror plane con-
taining the O(21)–C(21)–Re–N(1) bonds.
Fig. 2. ORTEP drawing of the [Re(CO)3(L3)]ꢀ complex anion (3) with
numbering scheme. Thermal ellipsoids are drawn at the 30% probability
level.

M. Allali et al. / Inorganica Chimica Acta 359 (2006) 2128–2134
2133
˚
Table 3
carbonyl bond lengths (mean 1.895 A) lie on the short side
2
ꢀ
˚
Selected bonds lengths (A) and angles (ꢂ) in [Re(CO)3(L )] (2) and
[Re(CO)3(L3)]ꢀ (3)
˚
of the range (1.89–2.03 A) found for other tricarbonyl-rhe-
nium compounds [18–20]. Conversely, the Re–N1 distances
(mean 2.254 A) are greater than the one reported for the
similar complex Re(CO)3(N-(3-aminopropyl)iminodiace-
tate) (2.239(3) A) [2]. As to the Re–O distances (2.121–
2.148 A), they are close to those found in related
[Re(CO)3(L2)]ꢀ
[Re(CO)3(L3)]ꢀ
˚
˚
Bond lengths (A)
Re–C(21)
Re–C(22)
Re–C(23)
Re–O(1)
Re–O(2)
Re–N(1)
C(1)–O(1)
C(1)–O(3)
C(3)–O(2)
C(3)–O(4)
C(21)–O(21)
C(22)–O(22)
C(23)–O(23)
1.908(5)
1.886(5)
1.895(5)
2.136(3)
2.121(3)
2.249(3)
1.277(6)
1.227(6)
1.270(5)
1.237(5)
1.147(6)
1.152(6)
1.156(6)
1.903(6)
1.896(5)
1.883(6)
2.126(3)
2.148(3)
2.258(4)
1.260(5)
1.239(5)
1.270(5)
1.232(5)
1.151(6)
1.156(6)
1.151(7)
˚
˚
compounds where a carboxylate oxygen is coordinated
trans to a carbonyl ligand. The rather large deviations from
the idealized octahedral geometry (bond angle ranges: cis
77.2–100.3ꢂ; trans, 171.7–176.8ꢂ) can be ascribed to the
constraints imposed by ring closure, the O–Re–N bite
angle being ꢂ77.5ꢂ.
The ligand side-chains keep the nitrophenyl group at a
large distance from the core of the molecule and precludes
any coordinative or hydrogen-bonding interactions with
components near the coordination sphere. In compound
3 containing an o-nitrophenyl group, intramolecular
hydrogen bonding between the nitro O(5) atom and the
Bond angles (ꢂ)
C(21)–Re–N(1)
C(22)–Re–N(1)
C(23)–Re–N(1)
O(1)–Re–N(1)
O(2)–Re–N(1)
C(21)–Re–C(22)
C(21)–Re–C(23)
C(21)–Re–O(1)
C(21)–Re–O(2)
C(22)–Re–C(23)
C(22)–Re–O(1)
C(22)–Re–O(2)
C(23)–Re–O(1)
C(23)–Re–O(2)
O(1)–Re–O(2)
Re–O(1)–C(1)
Re–O(2)–C(3)
O(1)–C(1)–O(3)
O(2)–C(3)–O(4)
Re–C(21)–O(21)
Re–C(22)–O(22)
Re–C(23)–O(23)
172.5(2)
96.2(2)
98.6(2)
77.18(11)
77.98(11)
90.0(2)
85.8(2)
98.2(2)
95.4(2)
88.4(2)
171.7(2)
100.3(2)
96.6(2)
77.55(12)
77.20(12)
86.9(2)
87.9(3)
97.7(2)
95.4(2)
86.0(3)
˚
free amino group (N(2)ꢃ ꢃ ꢃO(5) = 2.593(6) A, N(2)–
Hꢃ ꢃ ꢃO(5) = 131ꢂ) contributes to keeping the aromatic ring
coplanar with the C(7)–N(2) bond (C(7)–N(2)–C(11)–
C(16) torsion angle = ꢀ5.5(7)ꢂ). However, this hydrogen
bond does not seem to be a determining factor, since the
p-nitrophenyl ring in 2 adopts the same orientation
(C(6)–N(2)–C(11)–C(12) torsion angle = 4.0(7)ꢂ), even
though the nitro group does not participate in inter- or
intramolecular hydrogen bonding. In both cases, crystal
93.7(2)
96.8(2)
172.0(2)
175.5(2)
97.9(2)
176.8(2)
173.8(2)
96.3(2)
˚
packing leads to p–p interactions of 3.8 A between aro-
79.67(12)
118.7(3)
118.9(2)
125.2(4)
123.6(4)
177.4(5)
177.3(5)
176.5(4)
80.69(12)
119.7(3)
117.9(3)
124.9(4)
124.8(4)
179.1(5)
177.6(5)
177.4(7)
matic moieties of adjacent complexes. Since the nitro group
is essentially free, it should offer, after conversion into an
amino group, an ideal site for functionalization or coupling
with a biomolecule.
In both structures, the lattice water molecule forms O(7)–
Hꢃ ꢃ ꢃO bonds with free carboxylate oxygens O(3) and O(4) of
˚
different molecules (Oꢃ ꢃ ꢃO = 2.78–2.83 A,O–Hꢃ ꢃ ꢃO = 165–
172ꢂ). At the same time, it acts as the acceptor in N–Hꢃ ꢃ ꢃO
hydrogen bonds from the free amino group N(2) or the
[Et3NH]+ cation. In 3, where the amino group is already
hydrogen-bonded to the ortho nitro group, the hydrogen
Corresponding bond lengths and angles in 2 and 3 are
very similar (see Table 3) and compare well to those
observed for related complexes [5,6,15c,18–20]. The Re-
1
1'
0
1
2
3
4
5
6
7
8
9
time (min.)
Fig. 3. HPLC traces and retention times of the tricarbonyl complexes 1 (rhenium complex, UV, 220 nm, Tr = 2.64 min) and 10
radiometric detection, Tr = 2.97 min). Similar results (not shown) were obtained for 3 (Tr = 2.51 min) and 30 (Tr = 2.87 min).
(
99mTc complex,

2134
M. Allali et al. / Inorganica Chimica Acta 359 (2006) 2128–2134
bond to water is formed by the [Et3NH]+ cation
UK, fax: +44 1223 336 033, e-mail: deposit@ccdc.cam.
ac.uk or http://www.cam.ac.uk.
˚
(N(4)ꢃ ꢃ ꢃO(7) = 2.771(6) A, N(4)–Hꢃ ꢃ ꢃO(7) = 168ꢂ). In 2,
this role is played by the free amino group
˚
(N(2)ꢃ ꢃ ꢃO(7) = 3.041(5) A , N(2)–Hꢃ ꢃ ꢃO(7) = 155ꢂ), while
Acknowledgement
the [Et3NH]+ ion is linked to the carboxylate O(4) atom
˚
´
(N(4)ꢃ ꢃ ꢃO(4) = 2.785(5) A, N(4)–Hꢃ ꢃ ꢃO(7) = 170ꢂ).
The authors thank the C.M.I.F.M. (Comite Mixte Inter
Universitaire Franco-Marocain) for financial support (Pro-
ject MA/02/35).
3.4. 99mTc-labeling studies
Considering our interest in potential medical applica-
tions, we prepared the analogous 99mTc-complexes 10 and
30. Ligands H2L1 and H2L3 were radiolabelled with the pre-
cursor fac-[99mTc(CO)3(H2O)3]+. After 30 min at 80 ꢂC
References
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[
99mTc(CO)3(H2O)3]+ had disappeared completely and the
presence of a single new peak could be noticed in the radio-
chromatogram. Complexes 10 and 30 were both obtained in
an excellent radiolabelling yield (>95%). Since the retention
time of the 99mTc-complex 10 (and 30) is similar to that of
the ‘‘cold’’ Re-complex 1 (and 3) (see Fig. 3), it may be
assumed that identical structures are adopted by the species
generated at the tracer level and the complex produced and
characterized on the macroscopic scale. The differences
between the Re(CO)3 and the 99mTc(CO)3 species are
explained by the distance separating the UV/Vis and the
radiodetector in the instrument [21].
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4. Conclusion
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Our tridentate chelating systems NO2Ph-EDDA and
NO2Ph-PDDA stabilize the fac-[Re(CO)3]+ moiety, form-
ing well-defined complexes with a l:l metal-to-ligand ratio.
These ligands act as tridentate species by coordination via
the nitrogen of the iminodiacetic acid unit and two oxygens
of monodentate carboxylate groups. The structures of the
complexes consist of mononuclear anions with a distorted
octahedral geometry, the nitro group of the aromatic ring
(linking site model) remaining uncoordinated. Studies at
the n.c.a level have shown that it is possible to prepare
the analogous 99mTc compounds. Therefore, the high affin-
ity of these ligands for the fac-[M(CO)3]+ core (M = 99mTc,
Re), coupled with the easiness of their derivatization (by
reduction of the nitro group into amino group), implies
that utilization of these ligand systems are promising model
compounds for the development of target-specific radio-
pharmaceuticals for diagnosis and therapy.
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Inorg. Chem. 40 (2001) 5147.
[20] M. Lipowska, R. Cini, G. Tamasi, X. Xu, A.T. Taylor, L.G. Marzilli,
Inorg. Chem. 43 (2004) 7774.
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Spingler, N. Metzer-Nolte, R. Alberto, Org. Biomol. Chem. 2 (2004)
2593.
5. Supplementary material
Crystallographic data for [Et3NH][Re(CO)3(L2)] Æ H2O
(2) and [Et3NH][Re(CO)3(L3)] Æ H2O (3) have been depos-
ited with the Cambridge Crystallographic Data Centre,
CCDC Nos. 286365 and 286366, respectively. Copies of
these information may be obtained free of charge on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ,