Diazenide and hydrazide(2-) derivatives of the [Re(CO)3]+ core.

Article abstract of DOI:10.1039/b407708c

Reaction of [ReBr3(CO)3]2- with aryldiazonium salts gives the Re(iii) diazenide complexes [ReBr2(NNC6H4R-4)(CO)2]-. The attachment of a PhNHCS tethering group to pyridyl hydrazine generates a HYNIC related proligand which gives a stable chelated pyridyliu

Full text of DOI:10.1039/b407708c

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C O M M U N I C A T I O N
Diazenide and hydrazide(2−) derivatives of the [Re(CO)3]+ core
Roger Alberto,a Andrew R. Cowley,b Jonathan R. Dilworth,*c Paul S. Donnellyc and
Jennifer Prattc
a
Institute of Inorganic Chemistry, University of Zürich, Winterhurerstrasse 190, CH-8057 Zürich,
Switzerland
b
Chemical Crystallography Laboratory, University of Oxford, 12 Mansfield Road, Oxford,
UK OX1 3TA
c
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford,
UK OX1 3TA. E-mail: jon.dilworth@chem.ox.ac.uk; Fax: +01865-272690; Tel: +01865-285151
Received 21st May 2004, Accepted 22nd July 2004
First published as an Advance Article on the web 29th July 2004
1H NMR resonances for the diazonium aryl protons in the expected
Reaction of [ReBr3(CO)3]2− with aryldiazonium salts gives
the Re(III) diazenide complexes [ReBr2(NNC6H4R-4)(CO)2]−.
The attachment of a PhNHCS tethering group to pyridyl
hydrazine generates a HYNIC related proligand which gives
a stable chelated pyridyliumthiocarbazide(2−) derivative of the
[Re(I)(CO)3]+ core.
region. The IR spectrum for the complex as a nujol mull with
R = H shows strong bands due to the C–O stretching vibrations as
expected. The ES MS spectra show the mass ions at the expected
m/z value, and the fact that peaks for diazenide species are observed
in donor solvents confirms that the diazenide ligand is retained
in such solvents. A representation of the crystal and molecular
structure of the complex with R = CO2Et is shown in Fig. 1 together
with a summary of selected bond lengths and angles.
Certain radioisotopes of rhenium offer potential in the development
of targeted radionuclide therapy of cancer. Both rhenium-188 and
rhenium-186 are -emitters with nuclear properties suitable for
therapeutic applications.1–3 The recently developed rhenium-188
generator is clinically convenient and provides an economic source
of the radionuclide as a dilute aqueous solution of [188ReO4]−.3 For
effective treatment, the radionuclide must be selectively delivered
to the tumour and this can be achieved by incorporating the radio-
nuclide into a coordination complex using a bifunctional chelate.
The chelate should be highly stable and possess a point of further
functionalisation to allow the attachment of biologically active
molecules that can act as targeting vectors.
The use of functionalised diazenide (NNAr, Ar = aryl or 2-
pyridyl) ligands for the targeting of potential radiopharmaceuticals
based on technetium4,5 or rhenium is well established, particularly
for the pyridyl (HYNIC) system.6–10 Although in the latter case there
are a number of technetium based systems which are in clinical
trials for imaging,11,12 analogous Re systems are less developed.13,14
The [Tc(CO)3]+ core has been shown to be an extremely
versatile precursor for the development of 99m-technetium radio-
pharmaceuticals, but much less attention has been directed towards
the chemistry of the rhenium analogues.15–18 Despite the wide range
of polydentate ligands that have been combined with the [M(CO)3]+
(M = Tc,Re) cores to provide sites for attachment of appropriate
biological targeting agents, the use of diazenide type ligands has
not been reported although pyridylhydrazine itself can act as a
bidentate ligand.17
We here report the use of two different approaches to the
introduction of diazenide and related ligands with N–N bonds onto
the well established rhenium(I) tricarbonyl core. The first deploys
diazonium salts to give the first reported diazenide derivatives
of this core. The second uses pyridylhydrazines with pendant
soft donors to give dimeric chelated complexes with an unusual
zwitterionic bidentate diazene ligand. Both approaches provide
the possibility of conjugation to a biological targeting group via an
amide linkage.
Reaction of [Et4N]2[ReBr3(CO)3] with diazonium salts
[4-RC6H4N2][BF4] (R = H, CO2Et, Cl) in methylene chloride leads
to isolation of the complexes [Et4N][ReBr3(NNC6H4R-4)(CO)2] in
good yield.† The complex with R = CO2Et models the way in which
a biologically active molecule can in principle be attached to the Re
carbonyl core via an activated ester. The bromide ligands provide
potential sites for introduction of other ligands should manipulation
of lipophilicity be required. The diazenides are obtained as pale
brown air stable crystalline solids. The formal oxidation state of
the rhenium is three but the complexes are diamagnetic showing
Fig. 1 ORTEP representation of the anion of (1) showing the atom
labelling scheme. Selected bond lengths (Å) and bond angles (°). Re(1)–
Br(1) = 2.5457(7), Re(1)–Br(2) = 2.5991(7), Re(1)–Br(3) = 2.5547(7),
Re(1)–C(1) = 1.975(8), Re(1)–C(2) = 1.940(7), Re(1)–N(1) = 1.806(6),
N(1)–N(2) = 1.209(8). Br(2)–Re(1)–C(1) = 94.64(19), Br(3)–Re(1)–C(1) =
80.35(19), Br(1)–Re(1)–N(1) = 97.50(17), Re(1)–N(1)–N(2) = 171.3(5),
C(2)–Re(1)–N(1) = 96.4(3). Other angles at metal close to 90°.
The geometry about rhenium is essentially octahedral with each
of the 2 CO ligands trans to bromide. The reaction involves nett
oxidative addition of the diazonium salt to the rhenium with elimi-
nation of [Et4N][BF4]. The diazenide ligand is singly bent, consis-
tent with its formally donating three electrons to the metal, and the
M–N and N–N distances lie within the range found for other Re(III)
diazenides such as [ReCl2(NNPh)(MeCN)(PPh3)2].19
Although complexes of the M(CO)3+ core have been reported with
pyridylhydrazine acting as a bidentate ligand,17 the attachment of one
or more soft donor groups could be advantageous in terms of kinetic
stability. It would also produce clearly defined complexes and open
the possibility of extending the HYNIC methodology to other metals.
Anumber of pyridylhydrazines with tethering groups attached to the
NH2 group of the hydrazine have therefore been prepared, and an
example is presented in Fig. 2, together with the abbreviation.
SHYNICH3 rapidly reacts with the carbonyl precursor,
[Et4N]2[ReBr3(CO)3], at room temperature in methanol to give a
yellow-green product, 2, which could be isolated by the addition
of water. X-ray quality crystals of 2 were obtained by diffusion of
Fig. 2 Structure of a tethered pyridylhydrazine showing abbreviation.
2 6 1 0
D a l t o n T r a n s . , 2 0 0 4 , 2 6 1 0 – 2 6 1 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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pentane into an acetone solution of the complex. An ORTEP view
of the structure of 2 appears in Fig. 3. The structure comprises
two pseudooctahedral rhenium carbonyl centres bridged by thione
sulfurs.TheRe–Redistanceof3.64Åandtheformalvalenceelectron
count suggest there is no Re–Re bonding. The bond distances within
the doubly deprotonated SHYNICH ligand are consistent with it
bearing a dinegative charge. This is partially compensated by the
uncoordinated pyridyl nitrogen bearing a proton, with an overall
neutral charge on the complex. The delocalized SHYNICH ligand
is essentially planar, and this precludes coordination to the three
non-carbonyl coordinated facially disposed sites on the Re(CO)3
core. Under the dilute conditions used for radiopharmaceutical syn-
thesis it is likely that a solvated monomeric species will be formed.
Acknowledgements
We are grateful to the EPSRC for financial support of P.S.D. and to
Hermann Starck GmBH for the generous gift of rhenium metal.
Notes and references
† [ReBr3(CO)3][NEt4]2 (0.05 g, 0.07 mmol) and [4-EtCO2C6H4N2][BF4]
(0.02 g, 0.07 mmol) were dissolved CH2Cl2 (40 mL). The orange mix-
ture was stirred at reflux under an atmosphere of nitrogen for 4 h. The
mixture was allowed to cool to room temperature and the volume was
reduced in vacuo to about 2 mL. Diethyl ether was added to precipitate
[Et4N][ReBr3(N2C6H4-4CO2Et)(CO)2]
1 as an orange-brown powder
which was collected by filtration and washed with diethyl ether, (0.02 g,
1
0.02 mmol, 30%). H NMR (300 MHz) (d6-DMSO):  8.02, 2H, AA′ BB′
3
system, ArH; 7.53, 2H, AA′ BB′ system, ArH; 4.29, 2H, q JHH = 7 Hz,
O–CH2CH3; 3.10, 8H, q, JHH = 7 Hz, [N(CH2CH3)4]+; 1.29, 3H, t,
3
3JHH = 7 Hz, CH2CH3; 1.12, 12H, t, JHH = 7 Hz, [N(CH2CH3)4]+. ESMS
3
(−ve ion mode): m/z = 658 = [ReBr3(N2C6H4-4CO2Et)(CO)2]−, m/z = 632
(100%) = [ReBr3(N2C6H4-4CO2Et)(CO)]−. IR (KBr): NN = 1458,1491,

CO = 1916, 1988, 2066, Re–NN = 1719.
[Et4N]2[ReBr3(CO)3 (0.100 g, 0.13 mmol) was dissolved in CH3OH
(5 mL). SHYNICH3 (0.032 g, 0.13 mmol) was added and the yellow
reaction mixture was stirred at room temperature under an atmosphere
of nitrogen for 30 min. Addition of water resulted in the formation of a
green-yellow precipitate which was collected by filtration and washed with
water to give [(Re(PhNHCSNNpyH)(CO3)3)2] as a green-yellow powder,
(0.054 g, 0.05 mmol, 81%). (Found: C, 35.0; H, 2.74; N, 10.52; calc’d for
1
Re2C30H22N8O6S2: C, 35.08; H, 2.16; N, 10.91.) H NMR (300 MHz) (d6-
acetone):  11.22, 1H, s, HNC6H5; 8.4, 1H, s, PhNH; 7.78, 1H, m, ArH; 7.70,
2H, d, J = 9 Hz ArH, 7.53–7.25, 4H, m, 4H, 7.02, 1H, m, ArH; 6.39, 1H, m,
ArH. ESMS (−ve ion mode): m/z = 1025 (10%) = [Re2(C24H21N8S2)(CO)6]−,
m/z = 513 (100%) = [Re(C12H10N4S)(CO)3]−.
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Fig. 3 Structure of complex (2) with atom labelling scheme and
hydrogen atoms omitted for clarity. Selected bond lengths (Å) and
angles (°): Re(1)–S(1) = 2.462(1), Re(1)–S(1)′ = 2.535(1), Re(1)–N(2) =
2.198(3), Re(1)–C(av) = 1.920(5), C(1)–S(1) = 1.790(4), C(1)–N(1) =
1.286(6), N(1)–N(2) =1.424(5). S(1)–Re(1)–S(1)′ = 82.35(1), Re(1)–
S(1)–Re(2) = 97.65(4), S(1)–Re(1)–N(2) = 76.6(1), C(13)–Re(1)–C(14) =
91.36(18).
The use of diazonium salts provides access to new anionic
diazenide derivatives of the Re(CO)3 core and bifunctionality is
available via carboxyl substituents on the diazenide aryl group.
Pryidylhydrazines with a thioamide tethering group react with
the same core to give dimeric thione-bridged complexes with an
unusual zwitterionic bidentate bonding mode for the pyridyldiazene
ligand. By analogy with the HYNIC system20,21 it is straightforward
to introduce an activated ester group in the pyridyl ring for target-
ing and this can be done without the use of protecting groups for the
hydrazine. This demonstrates that the HYNIC targeting strategy can
be adapted to lower oxidation state rhenium cores.
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Crystal data for complexes (1) and (2)
For [Et4N][ReBr3(N2C6H4-4CO2Et)(CO)2], 1, C19H29Br3N3O4Re,
M = 789.37, triclinic, a = 10.3204(3), b = 10.7293(4), c =
11.9771(5), U = 1257.7 Å3, T = 150 K, space group
, Z = 2,
P1
(Mo-K) = 9.625 mm−1, 18254 reflections measured, 5492
unique, (R = 0.0478). The final wR was 0.0488.
For [Re2(C12H11N4S)2(CO)6]·2CH3COCH3, 2, C36H34N8O8Re2S2,
M = 1143.24, triclinic, a = 10.1017(2), b = 10.1665(2), c =
22.2480(4) Å, U = 1986.27(7) Å3, T = 150 K, space group P1,
Z = 2, (Mo-K) = 6.255 mm−1, 27687 reflections measured, 8953
unique (Rint = 0.043) The final wR was 0.0336. CCDC reference
numbers 239543 and 239544. See http://www.rsc.org/suppdata/dt/
b4/b407708c/ for crystallographic data in CIF or other electronic
format.
21 W. Guo, G. H. Hinkle and R. J. Lee, J. Nucl. Med., 1999, 40, 1563.
D a l t o n T r a n s . , 2 0 0 4 , 2 6 1 0 – 2 6 1 1
2 6 1 1