Rhenium and technetium bi- and tricarbonyl complexes in a new strategy for biomolecule incorporation using click chemistry

Article abstract of DOI:10.1039/c4dt00684d

A versatile strategy to prepare fac-[M^I(CO)₃] ⁺ and cis-[M^I(CO)₂]⁺ (M = Re, ^99mTc) complexes was developed using Huisgen click chemistry and monodentate phosphine ligands to readily incorporate biomolecules and tailor the chemical properties.

Full text of DOI:10.1039/c4dt00684d

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Rhenium and technetium bi- and tricarbonyl
complexes in a new strategy for biomolecule
incorporation using click chemistry†
Thomas R. Hayes,a Benjamin B. Kasten,a Charles L. Barnesb and Paul D. Benny*a
Cite this: Dalton Trans., 2014, 43,
6998
Received 6th March 2014,
Accepted 27th March 2014
DOI: 10.1039/c4dt00684d
www.rsc.org/dalton
A versatile strategy to prepare fac-[MI(CO)3]+ and cis-[MI(CO)2]+ the triazole donor into the newly formed chelate for sub-
(M = Re, 99mTc) complexes was developed using Huisgen click chem- sequent metal complexation.7 “Click to chelate” uses an
istry and monodentate phosphine ligands to readily incorporate exchangeable strategy to generate unique chelates for tuning
biomolecules and tailor the chemical properties.
the chemical properties of functionalized targeting
molecules.8
In diagnostic nuclear medicine, 99mTc remains the most uti-
lized radionuclide due its ideal nuclear properties (t1/2 = 6.0 h,
γ = 140 keV (89%)) for single photon emission computed tomo-
graphy (SPECT), kit chemistry, and the portability of the
99Mo–99mTc generator system.1 A water soluble organometallic
complex, Alberto’s reagent fac-[99mTcI(OH2)3(CO)3]+, has proven
to be a versatile synthon due to its facile preparation via an
Isolink® kit and labile aquo ligands to accommodate a variety
of ligand types and denticity.2 Multiple strategies have
emerged from tridentate ligands to a combination of mono-
and bidentate ligands to saturate the coordination sphere of
fac-[99mTcI(CO)3]+.3 2 + 1 complexes have the flexibility to tailor
the chemical nature and in vivo properties by adjusting either
the mono- or bidentate ligands.4 This methodology can also
be extrapolated to multi-valent or orthogonal targeting mole-
cules using a combinatorial approach, compared to a single
targeting molecule.5
In the present report, the versatility of the multi-ligand and
“click to chelate” approaches were combined to provide tunable
complexes for the fac-[MI(CO)3]+ core. Two NO bidentate ligand
systems were explored in conjunction with a monodentate
phosphine ligand to demonstrate the feasibility of combining
these approaches. A pyridine based NO bidentate ligand, pico-
linic acid (pic) was utilized as a model with the fac-[MI(CO)3]+
core followed by a “click to chelate” NO bidentate ligand pre-
pared from benzylazide and propiolic acid.9 The CuAAC
formed chelate was envisioned to have similar coordination
mode and strength as pic, while readily allowing incorporation
of azide-functionalized targeting molecules without synthetic
modification. Phosphines (PR3) were selected for their coordi-
nation potency with low valent 99mTc/Re carbonyl complexes
and chemical flexibility of the R substituents. PR3’s also
provide an avenue to trans labialize a carbonyl for subsequent
PR3 substitution to yield 2 + 1 + 1 cis-bicarbonyl-trans-phos-
phine complexes as previously observed with ReI.10
In radiopharmaceuticals, the CuI catalyzed azide alkyne
cycloaddition (CuAAC) reaction has emerged as an important
technique to improve the design and preparation for coupling
a chelate or radionuclide to a targeting molecule.6 CuAAC strat-
egies are applied in fac-[MI(CO)3]+ (M = 99mTc, Re) chemistry
for ligand design and coupling of radioactive complexes. Pio-
neered by Schibli and Mindt, “click to chelate” provides a versa-
tile strategy using CuAAC to rapidly assemble chelates on
azide- or alkyne-functionalized molecules, while incorporating
A stepwise strategy was used to probe the complexation for-
mation of NO and PPh3 (model phosphine) ligands with the
fac-[ReI(CO)3]+ core. The initial step involved the formation of
the NO-pic precursor fac-[ReI(OH2)(CO)3(pic)], 1, from the
addition of pic to fac-[ReI(OH2)3(CO)3](SO3CF3) in the presence
of NaHCO3 (Scheme 1).3a One equivalent of PPh3 was added to
aWashington State University, 100 Dairy Rd, Pullman, WA, USA.
E-mail: bennyp@wsu.edu; Fax: +1-509-335-8867; Tel: +1-509-335-3858
bUniversity of Missouri, 125 Chemistry, Columbia, MO, USA.
E-mail: barnesch@missouri.edu; Fax: +1-573-882-2754; Tel: +1-573-882-2962
†Electronic supplementary information (ESI) available: Full experimental
details, characterization data and crystallographic tables. CCDC 983202–983206.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4dt00684d
Scheme 1 fac-[ReI(CO)3]+ complexes with picolinic acid. (a) PPh3.
EtOH, 70 °C, 18 h. (b) PPh3, mesitylene, 169 °C, 4 h.
6998 | Dalton Trans., 2014, 43, 6998–7001
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1 at 70 °C to form the 2 + 1 complex, fac-[ReI(CO)3(pic)(PPh3)], conformers due to the orientation of the benzyl (Bn) group,
2, in moderate yields (53%). The addition of a second equi- either towards or away from the coordinated water. Slight
valent of PPh3 and increasing the reaction temperature con- shifts in the triazole proton (8.49, 8.55 ppm) and the CH2
verted the 2 + 1 product, 2, into the 2 + 1 + 1 cis–trans- group (5.76, 5.74 ppm) were observed in a 2 : 1 ratio, respect-
[ReI(CO)2(pic)(PPh3)2], 3, in excellent yield (92%). Characteri- ively. The more favorable Bn conformer is most likely oriented
zation of 2 and 3 correlated with the previously reported data towards the coordinated water as indicated in the X-ray struc-
using alternative conditions and starting materials.11 ture. The addition of PPh3 yielded the corresponding 2 + 1
Additional analytical data for 2 and 3 and single crystal X-ray product, fac-[ReI(CO)3(4)(PPh3)], 6, in excellent yield (91%).
1
diffraction experimental parameters with ORTEP drawings are Upon PPh3 coordination, H NMR indicated the conversion to
provided in the ESI.†12 The structure of 2 exhibited a distorted a single species in 6 with shifts of the triazole (7.61 ppm) and
octahedral geometry comparable to similar
2
+
1
fac- ABq splitting of CH2 (5.42 ppm).
Unlike the conversion of 2 to 3, excess PPh3 (5 equiv.) at
[ReI(CO)3(NO)(L)] complexes, but with slightly elongated trans
(Re(1)–C(27) 1.947 Å) and (Re(1)–P(1) 2.4975 Å) bonds.13 3 also high temperature for a prolonged period was required to
exhibited similar bonding of pic, but contained nearly equidi- convert 6 into the 2 + 1 + 1 complex, cis–trans-[ReI(CO)2(4)-
stant trans Re–P bonds (Re–P 2.413, 2.418 Å) and a near linear (PPh3)2], 7, in good yield (69%). Steric interactions of the Bn
P(1)–Re(1)–P(2) bond angle (174.39°) correlating with other group of 4 with the entering PPh3 ligand may have impeded
1
trans PR3 Re complexes.10b,10c,14
substitution requiring more aggressive conditions. H NMR of
The CuAAC clicked NO bidentate ligand, 1-benzyl-1H-1,2,3- 7 showed shifts of the triazole singlet (6.64 ppm) and the CH2
triazole-4-carboxylic acid, 4, was similarly explored in a step- group to a singlet (5.06 ppm). 31P NMR exhibited a downfield
wise approach with the fac-[ReI(CO)3]+ core. Complete syn- shift from the 2 + 1 product 6 (19.76 ppm) to the 2 + 1 + 1
thesis, characterization, and single crystal X-ray experimental product 7 (23.96 ppm). X-ray structures of 5, 6, and 7 displayed
details for 5, 6, and 7 can be found in the ESI.† Complexation similar distorted octahedral geometries of coordinated 4 ana-
of 4 with fac-[ReI(OH2)3(CO)3](SO3CF3) gave the NO bidentate logous to complexes 1–3 (Fig. 1).12 Notably, 6 also exhibited a
complex, fac-[ReI(OH2)(CO)3(4)], 5, in moderate yield (49%) lengthening of the Re–P (2.5098 Å) and trans Re–C (1.951 Å)
1
(Scheme 2). Interestingly, H NMR of 5 revealed two different bonds. While the coordination of 4 remained constant through
the series, Bn interactions within the complex were clearly
evident in crystal structures. The Bn group is oriented towards
the aquo ligand in 5, shifted away from the PPh3 in 6, and
restricted to the equatorial plane by steric interactions in 7.
Radioactive 99mTcI complexes were prepared in a sequential
manner analogous to ReI analogs and analyzed by comparative
UV/radio-HPLC (Fig. 2 (4), Fig. S1 (pic)†). Complexation of fac-
[
99mTcI(OH2)3(CO)3]+ with NO bidentate ligands, pic (1 × 10−3
M) or 4 (5 × 10−3 M), was achieved by heating at 90 °C or 50 °C
for 1 h to give fac-[99mTcI(OH2)(CO)3(L)], L = pic (1a), 4 (5a), in
quantitative yields (>98%). Addition of PPh3 (10−3 M) to 1a or
5a at 60 °C for 1 h afforded the 2 + 1 product fac-[99mTcI-
(CO)3(L)(PPh3)], L = pic (2a), 4 (6a), in 93% and 81% yield,
respectively. Increasing reaction temperature (>90 °C) for 1 h
led to the quantitative formation of the 2 + 1 + 1 complex fac-
Scheme 2 fac-[ReI(CO)3]+ complexes with 4. (c) fac-[ReI(OH2)3(CO)3]-
(SO3CF3), pH 6, r.t., 18 h. (d) PPh3, EtOH, 60 °C, 16 h. (e) PPh3, CH2Cl2,
mesitylene, 169 °C, 24 h.
[
99mTcI(CO)2(L)(PPh3)2], L = pic (3a), 4 (7a). At intermediate
temperatures (60–90 °C), peaks for both bi- and tricarbonyl
Fig. 1 Crystal structures of (A) 5, (B) 6, and (C) 7 with thermal ellipsoids at 50% probability. Hydrogens have been omitted to improve clarity.
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multi-component and customizable complexes from the
fac-[MI(CO)3]+ core for radiopharmaceutical applications.
This worked was funded in part by the DOE, Radiochemistry
and Radiochemistry Instrumentation Program (#DE-FG02-08-
ER64672) and NIH/NIGMS (Institutional Award T32-GM008336).
Isolink® kits were graciously provided by Dr. Mary Dyszlewski
at Covidien.
Notes and references
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Fig. 2 Normalized and offset UV and radio-HPLC chromatograms
of 6 (tR = 22.3 min), 6a (tR = 22.5 min), 7 (tR = 22.9 min) and 7a
(tR = 23.2 min).
complexes were observed in the chromatograms. While a
mixture of bi- and tricarbonyl complexes is not ideal for radio-
pharmaceutical applications, temperature control can be uti-
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tricarbonyl complex at low temperatures or the 2 + 1 + 1 bicar-
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also be used to mitigate mixed complexes in a single sample.
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7a were >99% stable under both conditions. However, 6a
exhibited 95% stability with histidine and nearly complete
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steric interactions may impact the overall stability of 2 + 1 com-
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