Synthesis of phenyl-13C6-ethene

Article abstract of DOI:10.1002/jlcr.501

In an effort to prepare an improved carbon-rich target material for the accelerator production of ¹³N labelled ammonia for use in positron emission tomography (PET), sulfonated poly(styrene/divinylbenzene) has been evaluated. The preparation of this target material using naturally abundant carbon-12 compounds was investigated in an effort to optimize conditions for the preparation of the analogous carbon-13 target material which may provide a cost-effective method for producing nitrogen-13 labelled ammonia via proton irradiation. As part of this study, phenyl-13C6-ethene was synthesized in three steps starting from benzene-13C6.

Full text of DOI:10.1002/jlcr.501

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Labelled Cpd Radiopharm 2001; 44: 757–761.
DOI: 10.1002/jlcr.501
Research Article
Synthesis of Phenyl-13C6-ethene
Elizabeth M. Zippi*
Department of Chemistry and Physics, Louisiana State University in Shreveport,
Shreveport, LA 71115, USA
Summary
In an effort to prepare an improved carbon-rich target material for the
accelerator production of 13N labelled ammonia for use in positron emission
tomography (PET), sulfonated poly(styrene/divinylbenzene) has been evalu-
ated. The preparation of this target material using naturally abundant carbon-
12 compounds was investigated in an effort to optimize conditions for the
preparation of the analogous carbon-13 target material which may provide a
cost-effective method for producing nitrogen-13 labelled ammonia via proton
irradiation. As part of this study, phenyl-13C6-ethene was synthesized in three
steps starting from benzene-13C6. Copyright # 2001 John Wiley & Sons, Ltd.
Key Words: phenyl-13C6-ethene; styrene; positron emission tomography
Introduction
For the purpose of improving ammonia-13N production for use in
medical imaging, pyrolyzed carbon-13 enriched sulfonated poly(styrene/
divinylbenzene) is under investigation. In order to prepare the cabon-13
*Correspondence to: E. M. Zippi, Department of Chemistry and Physics, Louisiana State
University in Shreveport, Shreveport, LA 71115, USA.
Contract/grant sponsor: Cambridge Isotope Laboratories, Inc.
Contract/grant sponsor: Biomedical Research Foundation of Northwest Louisiana.
Contract/grant sponsor: Louisiana Board of Regents Support Fund; contract/grant number:
LEQSF (1998-01)-RD-B-13
Contract/grant sponsor: Louisiana Affiliate of the American Heart Association; contract/grant
number: LA-97-UG-02
Contract/grant sponsor: Louisiana State University in Shreveport
Copyright # 2001 John Wiley & Sons, Ltd.
Received 1 January 2001
Revised 29 May 2001
Accepted 5 June 2001

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E. M. ZIPPI
enriched polymer, the corresponding monomer was synthesized in three
steps starting from benzene-13C6 (Scheme 1).1–3
Optimization of the phenylethene synthesis was carried out
using naturally abundant carbon-12 reagents.4,5 For the preparation
of phenyl-13C6-ethene, bromobenzene-13C6, produced from reaction
of benzene-13C6 with 1,3-dibromo-5,5-dimethylhydantoin (DBMH)
and trifluoromethanesulfonic acid (triflic acid)1 was purified by
distillation and converted to 1-phenyl-13C6-ethanol by Grignard
Reaction with acetaldehyde.2 Subsequent dehydration of the alcohol
with potassium bisulfite yielded phenyl-13C6-ethene.3 The overall yield
of phenyl-13C6-ethene starting from benzene-13C6 was approximately
50%. Unreacted benzene-13C6 was recovered via distillation of
bromobenzene-13C6.
Experimental
General
When required, glassware and cannula were flame-dried prior to use.
NMR spectra were recorded on a Bruker AC 250 MHz FT-NMR
spectrometer. GC analyses were performed on a Gow-Mac Gas
Chromotograph Series 350 equipped with a Thermal Conductivity
Detector using a 20% DC 200 on Chrom.-P 80/100 mesh column. All
yields reported were determined by GC and corrected for purity.
Bromobenzene-13C6(1)
To a 250-ml pear-shaped flask equipped with magneticstribar and
condenser with drying tube attached, were added benzene-13C6
(4.9409 g, 58.8 mmol), freshly distilled dichloromethane (70 ml), triflic
acid (99+%, 5.0265 g, 33.5 mmol) and DBMH (9.7299 g, 34.0 mmol).
During the addition of the DBMH, the flask was covered with
aluminum foil. The cloudy, yellow mixture was allowed to reflux in
Scheme 1.
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 757–761

SYNTHESIS OF PHENYL-13C6-ETHENE
759
the dark for 2 h. A saturated solution of sodium bisulfite (35 ml) was
then added to the product mixture until the amber organic layer was
decolorized. The mixture was neutralized with 2 M sodium carbonate
(60 ml). The organiclayer was separated and the aqueous layer
extracted with dichloromethane. The combined organic extracts were
dried over magnesium sulfate and distilled to afford 7.47 g of
1
bromobenzene-13C6 (77% yield, 96.7% GC purity); H NMR: d 7.50
(m, 2H, ortho H0s), 7.25 (m, 3H, meta and para H0s).
1-Phenyl-13C6-ethanol (2)
Magnesium turnings (3.3 g, 135.7 mmol), a crystal of iodine and a
magnetic stirbar were placed in a flame-dried 100-ml three-necked
round-bottomed flask equipped with thermometer, reflux condenser and
addition funnel. The apparatus was then carefully flame-dried again and
kept under an argon atmosphere. Ether (21 ml) was introduced into the
flask through the addition funnel by cannula. Bromobenzene-13C6
(4.45 ml of mixture, 4.30 ml, 40.8 mmol) was then transferred to the
funnel via cannula and carefully added to the mixture at room
temperature. The beginning of the reaction was evidenced by the
disappearance of the iodine color which changed from light yellow to
gray, then finally to dark brown. The flask was placed in a warm water
bath to induce reflux. After 30 min of continuous reflux, the mixture was
placed in an ice bath and allowed to cool to 08C. To the addition funnel
was added a mixture of ether (7 ml) and acetaldehyde (5.0 ml,
89.2 mmol) by cannula. The acetaldehyde solution was slowly added
to the stirring Grignard reagent over a 63 min period with the
temperature held below 158C. The reaction mixture became milky
yellow and viscous after the addition. Ice water was added to quench the
reaction and magnesium salts were dissolved with the addition of 15%
sulfuricacid. The organiclayer was separated and the aqueous layer
extracted with diethyl ether. The combined organic layers were dried
over magnesium sulfate, and concentrated in vacuo to yield 4.31 g of
1-phenyl-13C6-ethanol (83% yield, 89.8% GC purity); 1H NMR: d 7.30
(m, 5H, Ar H0s), 4.85 (q, 1H, methine H), 2.10 (s, 1H, OH), 1.40 (d, 3H,
CH3).
Phenyl-13C6-ethene (3)
1-Phenyl-13C6-ethanol (4.55 g mixture, 4.08 g, 31.9 mmol), potassium
bisulfate (0.28 g), copper metal (0.08 g) and hydroquinone (spatula tip)
Copyright # 2001 John Wiley & Sons, Ltd.
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E. M. ZIPPI
were added to a 15-ml pear-shaped flask equipped with short-path
distillation apparatus with thermometer and magneticstirbar. The flask
was wrapped with aluminum foil and placed in an oil bath. With a
vapor temperature 51508C and oil bath temperature >2008C, the
distillate was collected. The organic layer was separated and the
aqueous layer extracted with diethyl ether. The combined organic
phases were dried over magnesium sulfate and concentrated to give
2.54 g of phenyl-13C6-ethene (72% yield, 81.7% GC purity); 1H NMR:
d 7.69 (m, 2H, ortho H0s), 7.53 (m, 3H, meta and para H0s), 6.99 (dd, 1H,
CH), 6.03 (dd, 1H, H cis to ring), 5.15 (dd, 1H, H trans to ring).
Conclusion
Phenyl-13C6-ethene, while commercially available, is prohibitively
expensive. Benzene-13C6, purchased for a moderate price, can be
converted to phenyl-13C6-ethene in three synthetic steps in about 50%
yield. This yield is somewhat higher than previously reported, where
phenyl-14C6-ethene was prepared from benzene-14C6 in 28% yield.2 It
should be noted that during optimization of the reactions, when using
freshly opened reagents, yields were slightly higher for the Grignard
reaction (91%) and the dehydration (80%). Phenyl-13C6-ethene will be
polymerized, sulfonated and pyrolyzed in a way similar to that
previously reported using naturally abundant carbon-12 reagents6–8 to
yield a porous carbon-13 matrix which will be evaluated as a potential
PET target material for the accelerator production of ammonia-13N.
Acknowledgements
The author acknowledges Cambridge Isotope Laboratories, Inc. for
supplying the benzene-13C6 by way of a competitive grant award, and
the Biomedical Research Foundation of Northwest Louisiana, the
Louisiana Board of Regents Support Fund [LEQSF(1998-01)-RD-B-
13], the Louisiana Affiliate of the American Heart Association (LA-97-
UG-02), and Louisiana State University in Shreveport for support of
this research. The author would further like to acknowledge George W.
Kabalka, N. Satyamurthy, Gerald T. Bida, Ronald M. Martin, Wayne
A. Gustavson, Rhonda L. Nugent, and the many undergraduate
research assistants who worked on the optimization of this synthesis.
Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 757–761

SYNTHESIS OF PHENYL-13C6-ETHENE
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Copyright # 2001 John Wiley & Sons, Ltd.
J Labelled Cpd Radiopharm 2001; 44: 757–761