Synthesis of [1,2-14c]trichloroacetic acid

Article abstract of DOI:10.1002/jlcr.505

A growing interest in the phytotoxic effects of trichloroacetic acid (TCA) has led us to develop a small-scale (< 1 mmol) one-pot synthesis of [1,2-¹⁴C]TCA with > 70% yield and specific activity of 3.7 GBq/mmol.

Full text of DOI:10.1002/jlcr.505

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Labelled Cpd Radiopharm 2001; 44: 811–814.
DOI: 10.1002/jlcr.505
Research Article
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Synthesis of [1,2- C]trichloroacetic acid
1
,
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3
1
M. Bubner *, K. Fuksov a! , M. Matucha , K.H. Heise and
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G. Bernhard
1
Forschungszentrum Rossendorf e.V., Institute of Radiochemistry,
PO Box510119, D-01314 Dresden, Germany
2
Institute of Nuclear Medicine, Charles University, Prague 2, Czech Republic
3
Institute of Experimental Botany, The Academy of Sciences of the Czech
Republic, Prague 4-Kr c$ , Czech Republic
Summary
A growing interest in the phytotoxic effects of trichloroacetic acid (TCA) has
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led us to develop a small-scale (51 mmol) one-pot synthesis of [1,2- C]TCA
with >70% yield and specific activity of 3.7 GBq/mmol. Copyright # 2001
John Wiley & Sons, Ltd.
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Key Words: [1,2- C]trichloroacetic acid; one-pot synthesis
Introduction
Trichloroacetic acid (TCA) – a secondary air pollutant formed in the
atmosphere by photooxidation of C -chlorocarbons – is considered to
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be an important phytotoxic stress factor which influences the health
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status of forests. Radioindicator techniques using [1,2- C]TCA have
often been employed to study the behaviourof TCA in the soil and its
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effects on conifers. However, [1,2- C]TCA of high specific activity is
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–6
not commercially available and the methods described in the literature
*Correspondence to: M. Bubner, Forschungszentrum Rossendorf e.V., Institute of Radio-
chemistry, PO Box 510119, D-01314 Dresden, Germany.
Contract/grant sponsor: Grant Agency of the Czech Republic; contract/grant number: 522/99/
1465;
Contract/grant sponsor: Framework of the agreement concerning scientific–technical co-operation
between Federal Republic of Germany and the Czech Republic; contract/grant number: X.244.2
Copyright # 2001 John Wiley & Sons, Ltd.
Received 2 April 2001
Revised 4 June 2001
Accepted 12 June 2001

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M. BUBNER ET AL.
do not lend themselves to small (51 mmol) scale synthesis at high
specific activity.
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The described synthetic methods are multistep syntheses starting
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from [ C]acetate, [ C]acetylene or[ C]acetaldehyde orthey only
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involve mono- C-substitution. Blanchard used photochlorination of
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[
2- C]acetic acid of low specific activity with subsequent ion-exchange
chromatographic purification.
Using the publications of Sonia et al. and Abrams et al. as base and
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building upon ourown expe ri ence in synthesizing [ C]bromoacetic acid
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by direct halogenation of sodium [ C]acetate in the presence of
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sulphur , we have developed a method forthe small-scale synthesis of
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1,2- C]TCA. Potassium orsodium [1,2- C]acetate of maximum
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[
specific activity reacts almost quantitatively with gaseous chlorine to
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produce [1,2- C]TCA in the presence of sulphur, red phosphorus and
potassium iodide in a closed system.
Experimental
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Chemicals: Potassium [1,2- C]acetate of 3.7 GBq/mmol was obtained
!
from UVVVR (Prague, Czech Republic). Elemental chlorine was
synthesized from KMnO and HCl. Otherchemicals and solvents of
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analytical grade quality were obtained from Merck (Darmstadt,
Germany) and Fluka (Deisenhoven, Germany).
Apparatus for the synthesis: The synthesis was performed using the
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standard vacuum line and a thick-walled reaction tube (ampoule).
Analytical methods and separation techniques: The radioactivity was
measured with the LS 6500 liquid scintillation counter (Beckman,
USA). For purification of the product preparative HPLC was carried
+
out on a 250 ꢀ 8 mm polymerIEX column (8 mm) in H form (Watrex,
Praha, Czech Republic) with 0.02 M H PO as the eluent. The
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radiochemical purity was checked by a modified TLC method.
Thin-layer chromatograms were developed on cellulose F (Merck,
Darmstadt, Germany) with n-butanol–ammonia–water(84–1–14) and
measured with the Linear Analyzer LB-283 (Laboratorium Berthold,
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Wildbad, Germany). [1,2- C]TCA was analysed by GC-MS using the
Finnigan MAT ITD 800 (San Jose, USA) mass spectrometer in
connection with the gas chromatograph Varian 3400 (Walnut Creek,
USA) equipped with a DB-5 capillary column (30 m ꢀ 0.25 mm ID, film
3
thickness d 0.25 mm, J&W, Folsom, USA).
f
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 811–814

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SYNTHESIS OF [1,2- C]
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Table 1. Synthesis of [1,2- C]TCA from 0.1 mmol potassium [1,2- C]acetate
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No.
Reaction condition
Product composition
y
z
Catalyst
Cl (mmol)
2
T (8C)
Time (h)
DCA (%)
TCA (%)
1
2
3
4
5
6
7
S
S
P/S
1.0
2.06
2.0
2.2
2.0
2.0
2.2
5180
>180
5180
117
>180
180
180
2 ꢀ 6
2 ꢀ 7.5
3 ꢀ 6
22
4
18
550
>30
50
55
50
55
52
530
>50
30
ꢂ5
50
KI/P/S
KI/P/S
KI/P/S
KI/P/S/I2
>95
>98
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y
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1, 2- C]dichloroacetic acid.
[
[
z
14
1, 2- C]trichloroacetic acid.
Synthetic procedure: A 30 ml thick-walled glass ampoule was charged
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with 0.1 mmol potassium [1,2- C]acetate in 1 ml methanol, 0.1 mg red
phosphorus, 0.1 mg potassium iodide and a solution of 2 mg sulphur in
2
ml benzene. The solvents were removed by lyophilization, resulting in
a very fine, homogeneous mixture of the reaction components. Water-
free elemental chlorine (3 mmol) was added via the vacuum line and the
ampoule was sealed. The reaction was performed by heating the mixture
at 1808C in a bath of boiling diethylene glycol diethyletherfor24 h. The
non-reacted chlorine and hydrochloric acid were separated from the
reaction mixture by lyophilization at ꢁ808C. The residue was dissolved
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in 2 ml waterand distilled on the vacuum line. [1,2- C]TCA was
separated from the aqueous solution by HPLC. The concentration of
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[
>
1,2- C]TCA was 2 mmol/ml (7.4 MBq/ml). The average yield was
70%, the radiochemical purity >98%.
Results
The results of the experiments with varying catalyst composition,
reaction temperatures, and reaction times are shown in Table 1.
Experiment No. 7 offers the optimal conditions for the synthesis of
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[
1,2- C]TCA with maximum specific activity on the mmol-scale.
The self-decomposition of [1,2- C]TCA in aqueous solution is
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negligible. This has been shown by re-analysis after 1 year of storage
in refrigerator several times.
Acknowledgements
The research was supported via Grant No. 522/99/1465 of the Grant
Agency of the Czech Republic. Support was also provided in the
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 811–814

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M. BUBNER ET AL.
framework of the agreement concerning scientific–technical cooperation
between Federal Republic of Germany and the Czech Republic, Project
No. X.244.2 ‘Isotopically labelled compounds in the investigations of
biotransformations of important xenobiotics’ and is gratefully acknowl-
edged.
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Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 811–814