A solvent-free regioselective iodination route of ortho-carboranes

Article abstract of DOI:10.1039/b612465h

Tetraiodo-ortho-Carborane based x-ray contrast agents was prepared n a high yield, fast, clean, regioselective fashion by a solvent-free reaction of ortho-carboranes with iodine in sealed tubes. ortho-Carborane and its derivatives can be iodinated under electrophilic conditions using Lewis or Bronsted acid catalysts. The Pyrex tube was opened and gaseous HI removed by evaporation leaving the crude product as a solid. Almost all the excess iodine could be removed from the mixture by sublimation under reduced pressure avoiding the need for quenching with sodium metabisulfite and allowing further reuse of reagents. This solvent-free approach to the iodination of ortho-Carboranes is feasible and appears to be fairly generic for the synthesis of tetraiodinated products.

Full text of DOI:10.1039/b612465h

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A solvent-free regioselective iodination route of ortho-carboranes†
Albert Vaca,‡a Francesc Teixidor,a Raikko Kiveka¨s,b Reijo Sillanpa¨a¨c and Clara Vin˜as*a
Received 29th August 2006, Accepted 6th September 2006
First published as an Advance Article on the web 15th September 2006
DOI: 10.1039/b612465h
Tetraiodo-ortho-carborane based X-ray contrast agents can
be readily prepared in a high yield, fast, clean, regioselective
fashion by a solvent-free reaction of ortho-carboranes with
iodine in sealed tubes.
Scheme 1 General tetraiodination of 1-R-1,2-closo-C2B10H11 by reaction
with iodine in sealed tubes. For R= H, t= 4 h. For R= Me or Ph, t= 3.5 h.
Highly iodinated molecules have been of interest in materials
science and medical applications1 including the potential use of io-
dinated ortho-carboranes as next-generation radiopaque contrast
agents for X-ray diagnostic imaging.2 These compounds have a
much greater proportion of iodine in the structures compared to
the iodinated organic compounds currently used in X-ray contrast
agents. However, clean and effective syntheses are still the critical
issue for the consideration of highly iodinated ortho-carboranes as
realistic candidates for X-ray contrast agents.3
ortho-Carborane, 1,2-C2B10H12, and its derivatives, can be
iodinated under electrophilic conditions using Lewis or Brønsted
acid catalysts. Three methods have been developed for the trans-
formation of B–H vertices to B–I ones: (i) elemental iodine in the
presence of aluminium trichloride,4 or a mixture of acetic, nitric
and sulfuric acids to yield diiodinated compounds,5 (ii) iodine
monochloride and triflic acid to transform eight B–I vertices3a
and recently, (iii) a sequential combination of nucleophilic and
electrophilic reactions to generate the highest boron iodinated
ortho-carboranes: 3,4,5,7,8,9,10,11,12-I9-closo-1,2-C2B10H3 and
3,4,5,6,7,8,9,10,11,12-I10-1,2-closo-C2B10H2.6 Their extremely high
iodine content (around 90%) makes these compounds of particular
interest, but complications in the established syntheses of these
compounds still presents problems.
practical pathways to neutral molecular inorganic X-ray contrast
agents.
Regioselectively tetraiodinated ortho-carborane 8,9,10,12-I4-
1,2-closo-C2B10H8 (1) was easily obtained in a solvent-less reaction
just by heating 1,2-closo-C2B10H12 with four equivalents of I2
at 270
2
◦C for 24 h in a sealed tube. After the reaction
is complete, the PyrexTM tube was opened and gaseous HI
removed by evaporation leaving the crude product as a solid which
contained ca. 25% of 8,9,12-I3-1,2-closo-C2B10H9 and 75% of 1,
based on 1H{ B} NMR spectroscopy. Longer reaction times did
11
not improve substantially this result. Increasing the iodine ratio
led to greater reactivity and selectivity; heating 1,2-closo-C2B10H12
◦
with ten equivalents of I2 at 270 2 C for 4 h in a sealed tube
produced a solid containing 2% of 8,9,12-I3-1,2-closo-C2B10H9, ca.
93% of 1, and 4% of higher iodinated ortho-carboranes. Almost
all of the excess iodine (95%) could be recovered from the mixture
by sublimation under reduced pressure avoiding the need for
quenching with sodium metabisulfite and allowing further reuse
of reagents. The remaining solid was recrystallized from 1 : 1
1
ethanol/water to give pure 1 in a high yield. The 11B{ H}-NMR
shows a pattern 2 : 2 : 4 : 2 in which the resonances at higher and
lower field do not split in the 11B-NMR confirming that the four
iodine atoms are exocluster on four adjacent boron atoms. The
1H NMR spectrum of 1 reveals a singlet at 5.57 ppm assigned to
the two C-bonded H atoms. This signal is shifted to a higher
frequency by ca. 1 ppm relative to that in 1,2-closo-C2B10H12,
suggesting greater protonic character for these H atoms in the
tetraiodo species. To confirm the structure of 1, colourless crystals
were grown by the slow evaporation of a hexane/dichloromethane
solution and a single-crystal X-ray diffraction analysis10 (Fig. 1)
was undertaken.
The synthesis of 1 had previously been reported as a low
yield product by using chlorinated solvents and long workup
procedures.6b,11 Therefore the preparation and isolation of 1
described here is a much more convenient and efficient route.
To explore the versatility of the method, C-alkyl- and C-
aryl-substituted ortho-carboranes were iodinated under similar
conditions. Slightly shorter reaction times were needed for the
same degree of substitution compared to 1. Heating 1-R-1,2-
closo-C2B10H11 (R= Me, Ph) with I2 at 270 2 ◦C for 3.5 h gave
the corresponding 1-R-8,9,10,12-I4-1,2-closo-C2B10H7 (R= Me, 2;
Ph, 3) derivatives selectively in high yields (>75%). These were
The development of atom efficient, environmentally friendly
transformations which generate minimal waste is essential in order
to support sustainability of chemical synthesis through the 21st
century.7,8 Solvent-free synthesis is one approach which has shown
value in organic and organometallic synthesis9 for the selective
preparation of high value materials, and as an effective means of
waste minimization.
This work establishes new competitive syntheses of polyiod-
inated ortho-carboranes under solvent-free conditions. We have
explored the reactivity of ortho-carboranes with I2 under solvent-
free conditions in the absence of strong acids at high temperature
in sealed tubes (Scheme 1). The goal being to develop cleaner, more
aI.C.M.A.B. (C.S.I.C.), Campus U.A.B., 08193, Bellaterra, Spain. E-mail:
clara@icmab.es; Fax: +34 3580 5729; Tel: +34 3580 1853
bDepartment of Chemistry, P.O. Box 55, University of Helsinki, FIN-00014,
Helsinki, Finland
cDepartment of Chemistry, University of Jyva¨skyla¨, FIN-40351, Jyva¨skyla¨,
Finland
† Electronic supplementary information (ESI) available: Synthesis and
characterization of 1–5. See DOI: 10.1039/b612465h
‡ Albert Vaca is enrolled in the PhD program of the UAB, Spain.
4884 | Dalton Trans., 2006, 4884–4885
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satisfactory results in terms of selectivity. In each system investi-
gated, mixtures of highly iodinated ortho-carboranes were always
generated. Nevertheless, when the temperature was reduced to
170 2 ◦C, after 4 h, a reagent mixture of 1,2-closo-C2B10H12 and
I2 in 1 : 10 ratio produced a crude product containing 9,12-I2-
1,2-closo-C2B10H10 (ca. 85%), 8,9-I2-1,2-closo-C2B10H10 (ca. 13%)
11
and 8,9,12-I3-1,2-closo-C2B10H9 (ca. 2%), based on 1H and1H{ B}
NMR spectroscopy.
As a conclusion, our targeted synthesis and processing of
tetraiodinated ortho-carboranes with a solvent-free, high yield,
fast, clean and regioselective method has been achieved. Addi-
tionally, the procedure does not require any further solvent-based
workup and an excess of iodine is recovered and re-utilized. Work
is now underway to study the reported iodinated compounds
as X-ray contrast agents on methyl methacrylate polymerization
for bone cements and as building blocks for supramolecular
chemistry.
Fig. 1 Perspective view of the asymmetric unit of 1 with 30% ellipsoids.
Selected bond lengths (A): C(1)–C(2) 1.599(10), C(21)–C(22) 1.611(12),
B–I 2.139(10)–2.164(8).
˚
1
1
identified by H and 13C{ H} NMR spectroscopy and, for 3, by
X-ray analysis (Fig. 2) from crystals obtained by recrystallization
from hexane/dichloromethane.12 It is noteworthy that in the
iodination of 1-Ph-1,2-closo-C2B10H11, only B–H vertices from the
cluster have been activated, and in no case has C–I substitution in
the aromatic ring been observed.
Notes and references
1 P. J. Ell and S. Gambhir, in Nuclear Medicine in Clinical Diagnosis and
Treatment, 3rd edn, Churchill Livingstone, Oxford, UK, 2004.
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1996, 61, 9041; (b) PCT Int. Appl., WO9526353, 1995; Eur. Pat. Appl.,
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4 J. Li, C. F. Logan and M. Jones, Jr., Inorg. Chem., 1991, 30, 4866.
5 A. S. Batsanov, M. A. Fox, J. A. K. Howard, A. K. Hughes, A. L.
Johnson and S. J. Martindale, Acta Crystallogr., Sect. C, 2003, C59,
o74.
6 (a) G. Barbera`, F. Teixidor, C. Vin˜as, R. Sillanpa¨a¨ and R. Kiveka¨s,
Eur. J. Inorg. Chem., 2003, 1511; (b) G. Barbera`, F. Teixidor, C. Vin˜as,
R. Sillanpa¨a¨ and R. Kiveka¨s, Inorg. Chem., 2006, 45, 3496.
7 (a) R. Noyori, Chem. Commun., 2005, 1807; (b) M. Avalos, R. Babiano,
P. Cintas, J. L. Jime´nez and J. C. Palacios, Angew. Chem., Int. Ed., 2006,
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8 R. D. Rogers and K. R. Seddon, Science, 2003, 302, 792.
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10 Crystal data. 1: C2H8B10I4, M= 647.78, monoclinic, space group
Fig. 2 Perspective view of 3 with 30% ellipsoids. Selected bond lengths
(A): C(1)–C(2) 1.659(9), C(1)–C(13) 1.501(9), B–I 2.147(7)–2.155(7).
˚
The C-disubstituted counterparts, 1,2-R2-1,2-closo-C2B10H10
(R= Me, Ph) were iodinated in an analogous way and the crude
products obtained were analysed by ESI-MS. 1,2-Ph2-1,2-closo-
C2B10H10 underwent tetraiodination selectively after 3.5 h, whereas
1,2-Me2-1,2-closo-C2B10H10 was more susceptible to electrophilic
substitution and only 2.5 h were required for completion of the re-
action. This is consistent with both theoretical13 and experimental
results14 reported by Lipscomb and co-workers which showed that
the electron donating effect of methyl groups bonded to the Ccluster
atoms causes a uniform increase in electron density on the B atoms
while having little, or no effect on the sequence of substitution.
Having proven that this solvent-free approach to the iodination
of ortho-carboranes is feasible and appears to be fairly generic
for the synthesis of tetraiodinated products, we set out to study
whether the degree of substitution could be further tuned by
controlling the reaction temperature. Increasing the temperature,
and even the reaction time to several days, did not produce
˚
P21/c (no.◦14), a= 15.0422(5), b= 14.8814(5), c= 14.3581(5) A, b=
3
110.378(2) , U= 3012.90(18) A , Z= 8, Dc= 2.856 g cm−3, l(Mo-Ka)=
˚
8.235 mm−1, T= 173 K. F(000)= 2256. 18481 reflections measured,
6563 unique (Rint= 0.0581). R1(Fo)= 0.0417 [wR2(Fo2)= 0.0855] with
a goodness-of-fit of 1.049. CCDC reference number 611426. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/b612465h.
11 L. I. Zakharkin, V. I. Stanko and A. I. Klimova, Izv. Akad. Nauk SSSR,
Ser. Khim., 1966, 11, 1946.
12 Crystal data. 3: C8H12B10I4, M= 723.88, monoclinic, space group P21/n
◦
˚
(no. 14), a= 10.0569(4), b= 15.2555(5), c= 13.0206(5) A, b= 99.686(2) ,
U= 1969.18(13) A , Z= 4, Dc= 2.442 g cm−3, l(Mo-Ka)= 6.314 mm−1
,
3
˚
T= 173 K, F(000)= 1288. 11228 reflections measured, 4181 unique
(Rint= 0.0432). R1(Fo)= 0.0390 [wR2(Fo2)= 0.0744] with a goodness-
of-fit of 1.053. CCDC reference number 611427. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b612465h.
13 (a) M. D. Newton, F. P. Boer and W. N. Lipscomb, J. Am. Chem. Soc.,
1966, 88, 2353; (b) F. P. Boer, J. A. Potenza and W. N. Lipscomb, Inorg.
Chem., 1966, 5, 1301.
14 J. A. Potenza and W. N. Lipscomb, Inorg. Chem., 1966, 5, 1483.
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