High yield [125I]iodide-labeling of iodinated carboranes by palladium-catalyzed isotopic exchange

Article abstract of DOI:10.1016/S0022-328X(03)00344-9

We have recently shown the feasibility of palladium-catalyzed isotopic exchange between [¹²⁵I]iodide and 2-iodo-para-carborane. In this work we have modified the methodology and extended its application to a wider range of iodinated carboranes. Thus, by using Herrmann's catalyst in toluene at 100 °C, 2-I-p-, 3-I- o -, 9-I-o -, 9-I- m -carborane, 1-phenyl-3-I- o -carborane and 1,2-diphenyl-3-I-o -carborane have been radiolabeled with ¹²⁵ iodine in high to excellent yields.

Full text of DOI:10.1016/S0022-328X(03)00344-9

Journal of Organometallic Chemistry 680 (2003) 188Á192
/
www.elsevier.com/locate/jorganchem
High yield [125I]iodide-labeling of iodinated carboranes by palladium-
catalyzed isotopic exchange
Karl Johan Winberg a, Gemma Barbera` b, Ludvig Eriksson a, Francesc Teixidor b,
Vladimir Tolmachev a,*, Clara Vinas b, Stefan Sjoberg a,*
˜
¨
a Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 599, S-75124 Uppsala, Sweden
b Institut de Cie`ncia de Materials de Barcelona, CSIC, Campus de Bellaterra, Cerdanyola, 08193 Barcelona, Spain
Received 5 March 2003; received in revised form 4 April 2003; accepted 22 April 2003
Dedicated to Professor M.F. Hawthorne on the occasion of his 75th birthday
Abstract
We have recently shown the feasibility of palladium-catalyzed isotopic exchange between [125I]iodide and 2-iodo-para-carborane.
In this work we have modified the methodology and extended its application to a wider range of iodinated carboranes. Thus, by
using Herrmann’s catalyst in toluene at 100 8C, 2-I-p-, 3-I-o-, 9-I-o-, 9-I-m-carborane, 1-phenyl-3-I-o-carborane and 1,2-diphenyl-
3-I-o-carborane have been radiolabeled with 125iodine in high to excellent yields.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Isotopic exchange; Iodinated carboranes; [125I]iodide; Labeling; Palladium; Catalyst
1. Introduction
In this study we describe a broadening of the scope of
this labeling reaction and in order to create a more
general reaction, some major experimental changes had
to be implemented. The compounds investigated
(Scheme 1) are 2-I-p-(1), 3-I-o-(2), 9-I-o-(3), 9-I-m-
carborane (4), 1-phenyl-3-I-o-carborane (5) and 1,2-
diphenyl-3-I-o-carborane (6).
Radioioidination of 1, 3, and 4, via halogen exchange,
has previously been reported by Stanko and Iroshnikova
in a conference proceeding from 1970 [4].
There is a growing interest in the labeling of
polyhedral boron compounds (PBC) such as carboranes
and borate anions with halogens for biomedical applica-
tions such as in pharmacokinetic studies of boron
compounds for boron neutron capture therapy. This
area has recently been reviewed; see Tolmachev and
Sjoberg and references therein [1]. Radio-halogenation
¨
of negatively charged PBC’s using oxidative conditions
is a well-known procedure. Unfortunately this method is
less applicable to closo-carboranes.
Recently Grushin and co-workers [2] reported bromi-
nation of 9-I-closo-carborane by palladium-catalyzed
nucleophilic substitution. We have previously demon-
strated [3] that radioiodination of 2-I-p-carborane by a
palladium-catalyzed isotopic exchange reaction is pos-
sible and that the labeling reaction proceeds cleanly and
results in high yield.
2. Results and discussion
By using Herrmann’s catalyst (HC) (Scheme 1) in
toluene, we have found a very efficient and stable
catalytic system. All experiments were performed at
100 8C under argon and the obtained radiolabeling yield
for all non-C-substituted iodinated carboranes (1Á
exceeded 90% after 5 min (Fig. 1). Using the parent
iodinated carboranes (1Á4) as substrates the catalytic
/4)
/
* Corresponding authors. Tel.: ꢀ
3818.
E-mail address: ssj@kemi.uu.se (S. Sjoberg).
/46-18-471-3796; fax: ꢀ46-18-471-
/
system is stable and no indication of palladium pre-
cipitation could be seen.
¨
0022-328X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00344-9

K.J. Winberg et al. / Journal of Organometallic Chemistry 680 (2003) 188Á
/192
189
Scheme 1.
A representative TLC-chromatogram, showing the
radiolabeling of 3-iodo-ortho-carborane (2) after 5 min,
radiolabeled yields decreased with the addition of Q-salt
to the reactions.
In our attempts to optimize the labeling yield with
regard to the concentration of the iodinated carborane,
2-iodo-p-carborane (1) was used as a model compound.
Two different concentrations of 1, 0.01 and 0.001 mg
mlꢂ1, were compared with the standard concentration
of 0.1 mg mlꢂ1 (37 mmol mlꢂ1). The reactions were
allowed to proceed for 5 min. Using 0.01 mg mlꢂ1 of
iodinated-carborane the radiolabeled yield decreased to
71%, and with 0.001 mg mlꢂ1, the radiolabeled yield
decreased to 20%. These results indicate that a concen-
tration around 0.1 mg mlꢂ1 of iodinated carborane is
necessary for maintaining the excellent radiolabeling
yields.
In the first attempts to label ortho-carboranes, DMF
was used as a solvent. Despite the short reaction time,
degradation of the [125I]-labeled carborane was found
during the analysis. This was further investigated by
running the same reaction without addition of [125I]-
iodide. The 11B-NMR analysis of the reaction mixture
is shown in Fig. 2. The small peak at 0 (Rfꢁ
corresponds to non-labeled [125I]-iodide, and the peak at
Rfꢁ
0.7 corresponds to the labeled 3-[125I]iodo-o-car-
borane.
In separate blank experiments, either the iodinated
/
0.0)
/
carborane or the HC was excluded. As expected, in
those experiments no [125I]-iodinated-carborane (ortho,
meta or para) was detected.
Our previously reported [3] catalytic system
[Pd(dba)3/dppb;
tris(dibenzylideneacetone)-dipalla-
dium/1,4-bis-(diphenylphosphino)-butane] for this type
of reaction required stabilization by a quaternary
ammonium salt, tetra-n-butyl ammonium hydrogen
sulphate (Q-HSO4ꢂ) for efficient labeling of the 2-I-p-
carborane (1). However, under the present modified
reaction conditions, no addition of Q-salt was needed.
In none of the experiments did addition of Q-salt have
any positive influence on the reaction outcome. On the
contrary, in all experiments performed with the HC the
Fig. 1. [125I] radiolabeled yield as a function of time for 2-I-p-(1), 9-I-m-(4), 3-I-o-(2), and 9-I-o-carborane (3), using the general labeling procedure.

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K.J. Winberg et al. / Journal of Organometallic Chemistry 680 (2003) 188Á192
/
Fig. 2. Typical TLC-result of [125I] radiolabeling of 3-I-o-carborane (2) using the general labeling procedure after 5 min.
using compound 2 as the substrate reveals the presence
of the previously known 3-I-7,8-dicarba-nido-undecabo-
rate [5] derived from 2. To avoid this cluster partial
degradation process from closo to the nido-analogue,
DMF was replaced by toluene, a non-nucleophilic
solvent. As a result no degradation of the ortho-
carboranes 2 and 3 was observed.
By decreasing the amount of the HC, optimization of
the catalytic loading was investigated. Again 2-I-p-
carborane (1) was used as the model compound, and
in addition to the initial loadings of 5 mol.%; 1, 0.1 and
0.01 mol.% of catalyst were evaluated. See Fig. 3.
These results show that the loading of catalyst can be
decreased to 0.1 mol.% and still give a radiolabeling
yield of over 90%. To confirm this further, the four non-
Table 1
Radiolabeling yields for the parent iodinated carboranes using 5 and
0.1 mol.% of HC at 5 min reaction time
Entry Carborane
Yield: 5 mol.% HC Yield: 0.1 mol.% HC
1
2
3
4
2-I-p-carborane (1) 92.69
3-I-o-carborane (2) 98.19
9-I-o-carborane (3) 98.69
/
2.5
0.8
0
929
919
909
869
/
0.1
2.4
1.6
3.8
/
/
/
/
9-I-m-carborane
(4)
95.59
/
0.6
/
lower catalyst loading is quite feasible although the
yields are somewhat lower.
To get an indication of the steric tolerance of the
reaction, the two substituted carboranes, 1-phenyl-3-
iodo-ortho-carborane (5) and 1,2-diphenyl-3-iodo-
ortho-carborane (6) were labeled. In both cases, pre-
cipitation of palladium black could be seen. Despite the
similarity of the compounds, the two compounds behave
differently under these reaction conditions. The average
radiolabeling yield for 5 was 83% after 5 min of reaction
time. This yield decrease over time and after 20 min the
radiolabeled yield dropped to 58%. This could be
explained by the degradation of ortho-carborane to
nido-carborate (as shown for 3-iodo-ortho-carborane in
DMF). The initial radiolabeling yield for the di-sub-
stituted ortho-carborane 6 was lower, with an average
value of 65% after 5 min. This yield increases with time
and after 20 min the yield was 86%. By comparing the
labeling yields of 5 and 6 with that for 3-I-o-caborane
arylated iodinated carboranes (1Á4) were subjected to
/
this lower catalyst loading. As shown in Table 1, this
Fig. 3. Yield of [125I] radiolabeling of 2-I-p-carborane (1) as a function
of the amount of added catalyst. Five, 1, 0.1 and 0.01 mol.% of the HC
was used (reaction time 5 min).

K.J. Winberg et al. / Journal of Organometallic Chemistry 680 (2003) 188Á
/192
191
Scheme 2.
(2) (98% after 5 min of reaction), the steric interactions
seems to have an impact of the [125I]iodide-labeling rate.
As discussed previously [3] a likely mechanism for this
halogen exchange reaction is given in Scheme 2 for the
radioiodination of 9-I-o-carborane (3).
quently 200 ml of ethyl acetate was added to the reaction
vial. After mixing, samples for TLC analysis (1Á2 ml)
were collected. Blank experiments were also performed,
using exactly the same conditions, but neat toluene was
used instead of the stock solution HC, or neat acetoni-
trile was used instead of the solution of iodinated
carborane.
/
3. Experimental
3.1. Materials
3.3. Analytical techniques and purification
[
125I]-iodide was obtained from Amersham Pharmacia
Silica gel 60 F254 thin layer chromatography plates (E.
Merck, Darmstadt, Germany) were used for analysis.
Biotech UK Limited, with a specific activity of 644 GBq
mgꢂ1. HC (trans-di-m-acetatobis[2-(di-o-tolylphosphi-
no)benzyl]dipalladium) (II) and tetra-n-butyl ammoni-
um hydrogen sulphate (QHSO4) were purchased from
Lancaster Ltd. Acetonitrile (HPLC grade) was pur-
chased from Sigma-Aldrich Sweden AB and toluene was
distilled from sodium and benzophenone. 9-I-o-carbor-
ane was prepared according to the procedure described
by Jones and co-workers [6], and 2-I-p-carborane and 9-
I-m-carborane in analogy with the procedure described
by Hawthorne and co-workers [7] 3-I-o-carborane [6], 1-
phenyl-3-I-o-carborane [8] and 1,2-diphenyl-3-I-o-car-
borane [9] were synthesized according to previously
published procedures. All non-radioactive iodinated
carborane was characterized by 1H-, 13C- and 11B-
NMR and spectral data were found to be consistent
with those reported in the literature.
The reaction mixture (1Á2 ml) was applied on a TLC
/
plate. Rf values for all reaction mixtures were deter-
mined by using non-labeled authentic samples. As an
eluant, pentane was used for compounds 1 and 4
whereas ethylacetate/ether (1/1; v/v) was used for
compounds 2Á
/
3 and 5Á6. Any nido-carborane used
/
will stay on the base line of the chromatogram together
with unreacted [125I]-iodide ions. An eluted plate of non-
labeled carborane and NaI was developed by dipping it
into an acidified methanol solution of palladium (II)
chloride followed by heating. Distribution of radio-
activity along the TLC strips was measured on the
CycloneTM Storage Phosphor System (Packard Instru-
ments Company Inc., Downers Grove, US) and ana-
lyzed using the OptiQuantTM Image Analysis Software.
The labeled carboranes can easily be purified by
chromatography using a small silica column with the
same eluents as described for the TLC analysis.
3.2. General 125I-labeling procedure
The following stock solutions were prepared: iodi-
nated carboranes (37 mmol mlꢂ1) in acetonitrile. HC
(6.94 mg) was, prior to use, dissolved in 10 ml degassed
toluene (0.74 mmol Pd (II) HC) under argon.
4. Conclusion
For a typical labeling experiment, 0.25 MBq or 3.9ꢃ
/
10ꢂ7 mg (3.12ꢃ10ꢂ9 mol) of [125I]iodide was used.
/
Aqueous solution (5 ml) of sodium [125I]iodide (stabilized
with sodium hydroxide) and 100 ml of the acetonitrile
solution of iodinated carborane were transferred to a 2-
ml Eppendorf tube. The solvents were evaporated under
a flow of argon at 100 8C. After complete evaporation,
200 ml of HC-stock solution was added, still under a
flow of argon, and the reaction vial was sealed. The
reaction proceeded at 100 8C for 5 min, and subse-
We have demonstrated that by using HC in toluene,
the catalyzed isotopic exchange between the iodide of
iodinated carboranes and [125I]iodide, [125I]-labeled
carboranes are provided under mild conditions in high
to excellent radiolabeling yields. Further investigations
of the isotopic exchange reaction using different radio-
active isotopes and other substituted carboranes will be
carried out.

192
K.J. Winberg et al. / Journal of Organometallic Chemistry 680 (2003) 188Á192
/
[2] W.J. Marshall, R.J. Young, Jr., V.V. Grushin, Organometallics 20
(2001) 523.
[3] L. Eriksson, V. Tolmachev, S. Sjoberg, J. Label. Compd. Radio-
Acknowledgements
¨
This work has been performed with financial support
from Swedish Cancer Society (Cancerfonden) and IN-
TAS (grant 99-00806) and Generalitat de Catalunya
(project 2001/SGR/00337). We thank the Division of
Biomedical Radiation Sciences for their kind permission
to use their facilities and equipment for our work with
radioactive materials.
pharm. 46 (2003) 623.
[4] V.I. Stanko, N.G. Iroshnikova, Isotope exchange in various
aromatic iodine compounds. Inst. Biofiz., USSR. Nov. Metody
Poluch. Radioaktiv. Prep., Sb. Dokl. Simp. (1970), Meeting Date
1969, p. 486. Postoyan. Kom. Ispol’z. At. Energ. Mirnykh
Tselyakh, Warsaw, Poland, (in Russian).
[5] G. Barbera`, C. Vinas, F. Teixidor, A.J. Welch, G.M. Rosair, J.
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Hawthorne, Inorg. Chem. 34 (1995) 3491.
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