Synthesis of difluorobenzene double-labeled with tritium

Article abstract of DOI:10.1134/S1066362212050165

A procedure based on nuclear-chemical generation of free nucleogenic reactive species was developed for the synthesis of difluorobenzene double-labeled with tritium as a precursor for the generation of previously unknown difluorophenyl cations. Pleiades Publishing, Inc., 2012.

Full text of DOI:10.1134/S1066362212050165

ISSN 1066-3622, Radiochemistry, 2012, Vol. 54, No. 5, pp. 506–508. © Pleiades Publishing, Inc., 2012.
Original Russian Text © V.V. Avrorin, N.E. Shchepina, 2012, published in Radiokhimiya, 2012, Vol. 54, No. 5, pp. 467–469.
Synthesis of Difluorobenzene Double-Labeled with Tritium
V. V. Avrorinа and N. E. Shchepinab
а St. Petersburg State University, St. Petersburg, Russia
b Natural Science Institute, Perm State National Research University,
ul. Genkelya 4, Perm, 614990 Russia; e-mail: neshchepina@mail.ru
Received November 9, 2011
Abstract—A procedure based on nuclear-chemical generation of free nucleogenic reactive species was devel-
oped for the synthesis of difluorobenzene double-labeled with tritium as a precursor for the generation of previ-
ously unknown difluorophenyl cations.
Keywords: difluorobenzene, tritium-labeled compounds, nuclear-chemical generation of carbenium ions
DOI: 10.1134/S1066362212050165
and the development of a one-step route to unknown
and difficultly accessible tritium-labeled N-phenyl het-
erocyclic onium compounds, many of which are im-
portant biologically active substances [7, 8].
The nuclear-chemical method, discovered in the
middle of the XX century, offers a unique opportunity
to generate free carbenium ions by β-decay of tritium in
hydrocarbons [1–3]. Previously we performed a series
of studies on generation of nucleogenic phenyl cations
by β-decay of tritium both in fully tritiated benzene,
Six-membered nitrogen-containing heterocyclic
compounds are extremely important objects of biologi-
cal studies. Among these compounds are natural nico-
tinic acid derivatives (coenzymes, vitamins B2 and B6).
Enormous number of drugs contain a heterocyclic
pyridine ring (Piroxicam exhibiting anti-inflammatory
activity, Nifedipine and Amlodipine used for the treat-
ment of stenocardia, and Pinacidil used for treatment
of hypertonic disease) [9–11]. Introduction of fluorine
into the quinoline ring led to the discovery of a new
class of strong antibacterial drugs, those of the fluoro-
quinolone series, occupying a prominent place among
modern antibacterial chemotherapeutic agents [12–19].
–
β
C6T6 → [C6T5 He]+ → C6T5+ + 3He,
3
and in ditritiobenzene,
β–
C6H4T2 → C6H4T+ + 3He.
We also studied ion–molecule reactions of the gen-
erated free nucleogenic phenyl cations with various
classes of polycentered nucleophiles: organic, or-
ganometallic, and heterocyclic compounds [4–6].
A significant achievement of the nuclear-chemical
method was the discovery of the previously unknown
reaction of direct phenylation of the nitrogen atom in
six-membered heterocyclic derivatives (this particu-
larly concerns quinolinium derivatives)
In this connection, it was of particular interest to
perform nuclear-chemical syntheses of fluorinated het-
erocyclic derivatives. To introduce fluorine into the
benzene ring, we chose a new reactive species, fluori-
nated phenyl cation, which will be generated by the
β-decay of tritium in difluoroditritiobenzene:
In so doing, to generate a single kind of cations, it
is necessary to choose a difluoroditritiobenzene with
equivalent tritium atoms. This requirement is met in
506

SYNTHESIS OF DIFLUOROBENZENE DOUBLE-LABELED WITH TRITIUM
507
two difluoroditritiobenzene isomers: 1,4-difluoro-2,5-
ditritiobenzene and 1,2-difluoro-4,5-ditritiobenzene.
Difluoroditritiobenzene can be prepared via two
alternative pathways: hydrolysis of difluorophen-
ylenedilithium [20] with tritium-containing water and
catalytic replacement of halogen by tritium [21] in di-
fluorodibromobenzene. The disadvantages of the first
pathways are the need for using large excess of trit-
ium-containing water in hydrolysis and for performing
the reaction in diethyl ether, which is a strong nucleo-
phile and hence will compete with quinoline com-
pounds in reactions with difluorophenyl cation. Re-
moval of excess tritium-containing water and replace-
ment of the ether by a weak nucleophile, hexane, are
undesirable in operation with ultrasmall amounts of
labeled compounds. The second pathway is free of
these drawbacks, and specifically this pathway was
chosen for the synthesis of difluoroditritiobenzene.
Difluoroditritiobenzene was synthesized by the modi-
fied procedure involving halogen replacement by trit-
ium, catalyzed by Pd/BaSO4, in the presence of an
amine for binding the released hydrogen halide:
Scheme of the installation for the synthesis of difluoroditri-
tiobenzene: (1) vacuum stopcock, (2) three-way stopcock,
(3) ampule with tritium, (4) magnetic striker, (5) ampule
with molecular sieves, (6) reaction ampule, and (7) reaction
mixture and catalyst.
C6H2F2Br2 + 23H2 + (C4H9)3N → C6H4F2 H2
3
+ (C4H9)3N3H+Br–.
liquid nitrogen, 2.5 Ci of tritium was condensed. The
three-way stopcock was arranged in the position in
which the reaction ampule was connected with the am-
pule containing molecular sieves. The reaction ampule
was cooled with liquid nitrogen, and the ampule with
molecular sieves was allowed to warm up to room
temperature. After that, the three-way stopcock was
turned to seal the ampule with the molecular sieves,
and its contents were agitated by shaking for 1 h. The
ampule with the molecular sieves was replaced by a
clean empty ~0.5 cm3 ampule. The reaction ampule
was evacuated with cooling with liquid nitrogen, and
volatile hydrogenation products together with hexane
were distilled in a static vacuum into the newly at-
tached ampule cooled with liquid nitrogen.
The synthesis was performed on an installation
schematically shown in the figure. As starting com-
pound we used 1,4-dibromo-2,5-difluorobenzene, and
as a base for binding HBr, high-boiling tributylamine,
which allowed easy separation of difluorobenzene and
amine by simple vacuum distillation. The reaction am-
pule was charged with 5–10 mg of the catalyst (5% Pd/
BaSO4), a second ampule was charged with CaX mo-
lecular sieves, and both ampules were connected to a
synthesis installation. Ampules with molecular sieves
and with the catalyst were evacuated with heating to
~400 and ~160°С, respectively. The evacuation was
continued until the maximal rarefaction (~10–3 mm
Hg) was attained. After that, hydrogen was admitted
into the ampule with the catalyst to a pressure of
~0.5 atm. The ampule was kept for 10–15 min at
~160°C and cooled to room temperature, after which
the residual hydrogen and volatile hydrogenation prod-
ucts were removed in a vacuum. Then the reaction am-
pule was detached, and 50 μl of a hexane solution con-
taining 20 μmol of 1,4-dibromo-2,5-difluorobenzene
and 30 μmol of tributylamine was introduced. The am-
pule was cooled with liquid nitrogen and evacuated.
Into the ampule with molecular sieves, cooled with
The reaction products were analyzed by gas chro-
matography. In the chromatogram, there were only two
peaks belonging to hexane and difluorobenzene, sug-
gesting high chemical purity of the product obtained.
Its amount was determined by external normalization
to be 14.6 μmol, which corresponds to 73% yield
based on 1,4-dibromo-2,5-difluorobenzene. The activ-
ity of the product was measured by liquid β-ray radi-
ometry with a Beta-2 installation. The synthesized
1,4-difluoro-2,5-ditritiobenzene is characterized by the
RADIOCHEMISTRY Vol. 54 No. 5 2012

508
AVRORIN, SHCHEPINA
specific activity of 54 ± 5 mCi μmol–1, total activity of
788 ± 73 mCi, and tritium label multiplicity of 1.93 ±
0.18.
and Badun, G.A., Perspekt. Mater., 2011, no. 10,
pp. 339–344.
9. Gilchrist, T.L., Heterocyclic Chemistry, Harlow (UK):
Longman, 1992, 2nd ed.
10. Pozharskii, A.F., Soldatenkov, A.T., and Katritz-
ky, A.R., Heterocycles in Life and Society, New York:
Wiley, 1997.
11. Joule, J.A. and Mills, K., Heterocyclic Chemistry,
Blackwell Science, 2000, 4th ed.
ACKNOWLEDGMENTS
The study was financially supported by the Russian
Foundation for Basic Research, project no. 10-03-
00685-а.
12. Chemistry of Organic Fluorine Compounds: II ACS
Monograph 187, Washington, DC, 1995.
13. Padeiskaya, E.N. and Yakovlev, V.P., Ftorkhinolony
(Fluoroquinolines), Moscow: Bioinform, 1995.
REFERENCES
1. Nefedov, V.D., Sinotova, E.N., and Toropova, M.A.,
Khimicheskie posledstviya β-raspada (Chemical Conse-
quences of β-Decay), Moscow: Atomizdat, 1978,
pp. 126–179.
2. Nefedov, V.D., Sinotova, E.N., and Toropova, M.A.,
Izv. Sib. Otdel. Akad. Nauk SSSR, Ser. Khim. Nauk,
1980, no. 3, pp. 35–43.
14. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Novaya Volna, 2005, 15th ed.
15. Wright, D.H., Brown, G.H., Peterson, M.L., and
Rotschafer, J.C., J. Antimicrob. Chemother., 2000,
vol. 46, pp. 669–683.
16. Noreddin, A.M., Haynes, V.L., and Zhanel, G.G.,
J. Pharm. Pract., 2005, vol. 18, pp. 432–443.
17. Melhus, A., Expert Opin. Drug Saf., 2005, vol. 4,
pp. 299–309.
3. Speranza, M., Chem. Rev., 1993, vol. 93, pp. 2933–
2980.
4. Shchepina, N.E., Nefedov, V.D., Toropova, M.A., et al.,
Tetrahedron Lett., 2000, vol. 41, pp. 5303–5306.
18. Murray, T.S. and Baltimore, R.S., Pediatr. Ann., 2007,
vol. 36, pp. 336–342.
5. Shchepina, N.E., Avrorin, V.V., Badun, G.A., et al.,
19. Boogaard, J., Kibiki, G.S., Kisanga, E.R., et al., Anti-
microb. Ag. Chemother., 2009, vol. 53, pp. 849–862.
Khim. Geterotsikl. Soedin., 2009, no. 7, pp. 1008–1014.
6. Shchepina, N.E., Avrorin, V.V., Badun, G.A., et al.,
Vestn. Mosk. Gos. Univ., Ser. 2: Khim., 2009, vol. 50,
no. 5, pp. 311–316.
7. Shchepina, N.E., Avrorin, V.V., Badun, G.A., et al.,
Khim. Geterotsikl. Soedin., 2010, vol. 46, no. 5,
pp. 692–698.
20. Talalaeva, T.V. and Kocheshkov, K.A., Metody ele-
mentoorganicheskoi khimii (litii, natrii, kalii, rubidii,
tsezii (Methods of Organometallic Chemistry (Lithium,
Sodium, Potassium, Rubidium, Cesium)), Moscow:
Nauka, 1971, book 2, pp. 565–1192.
21. Shchepina, N.E., Avrorin, V.V., Badun, G.A., et al.,
8. Shchepina, N.E., Avrorin, V.V., Aleksandrova, G.A.,
Radiokhimiya, 2007, vol. 49, no. 6, pp. 551–553.
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