Polyfluoroalkylation of pyrrole with 1,2-dibromotetrafluoroethane activated by sulfur dioxide

Article abstract of DOI:10.1007/s11172-010-0135-y

A possibility of the homogeneous catalytic fluoroalkylation of pyrrole with Freon BrCF₂CF₂Br using a nitrous base-sulfur dioxide system was shown. The influence of pK_a of bases on the occurrence of these processes was studied. The ion-radical mechanism of the processes was substantiated.

Full text of DOI:10.1007/s11172-010-0135-y

Russian Chemical Bulletin, International Edition, Vol. 59, No. 3, pp. 577—580, March, 2010
577
Polyfluoroalkylation of pyrrole
with 1,2ꢀdibromotetrafluoroethane activated by sulfur dioxide
V. G. Koshechko, L. A. Kiprianova, and L. I. Kalinina
L. V. Pisarzhevsky Institute of Physical Chemistry, National Academy of Sciences of Ukraine,
31 prosp. Nauki, 03028 Kiev, Ukraine.
Fax: +38 (044) 525 6216. Eꢀmail: lkipr@ inphyschemꢀnas.kiev.ua
A possibility of the homogeneous catalytic fluoroalkylation of pyrrole with Freon
BrCF2CF2Br using a nitrous base—sulfur dioxide system was shown. The influence of pKa of
bases on the occurrence of these processes was studied. The ionꢀradical mechanism of the
processes was substantiated.
Key words: Freons, fluoroalkylation, pyrrole, sulfur dioxide.
Search for new methods for the introduction of perꢀ
and polyfluoroalkyl groups into heterocyclic compounds
attracts considerable interest of many researchers, since
these products can be used as biologically active comꢀ
pounds.1—5 One of the promising sources of polyfluoroꢀ
alkyl groups can be Freons containing along with fluorine
atoms several atoms of other halogens, which substantialꢀ
ly extends their synthetic potentialities.6—10 However, as
known, Freons possess very low reactivity and are inert
toward many organic substrates, which requires the search
for and the use of various methods of activation of the
organic substrate—Freon interaction by increasing the reꢀ
activity of either the molecule that must be fluoroalkylatꢀ
ed, or Freon (the latter is usually carried out by the geꢀ
neration of highly reactive free fluoroalkyl radicals
from Freon).
In the case of azoles, the introduction of perfluoroꢀ
alkyl groups is carried out mainly involving perfluoroalkyl
radicals, which are generated from perfluoroalkyl halides
photochemically,3,11 electrochemically,12,13 and by the
chemical interaction of Freons with derivatives of tetravaꢀ
lent sulfur.2,14—18 As a rule, perfluoroalkyl iodides with
much higher reactivity than Freons were used as fluoroꢀ
alkylating agents, and azole salts with alkaline metals were
fluoroalkylated instead of azoles themselves.6,7,19
phenols (ArXH, X = S, O) can successfully be activated
using simultaneously organic bases and electron transfer
mediators from the substrate to Freon with the generation
from the latter of highly reactive fluoroalkyl radicals. Subꢀ
stituted pyridines were used as organic bases, because they
are capable of hydrogen bonding with the SH and OH
groups and, hence, enhancing the electronꢀdonor ability
of ArXH due to the equilibrium shift
toward thiophenolate and phenolate anions (in the comꢀ
position of the ionic complex) with a lower oxidation poꢀ
tential. However, only this effect was insufficient for the
process to occur, and mediators (SO2, I2, etc.) were introꢀ
duced to provide electron transfer.17—19
An analogous approach has well recommended itself and
makes it possible to efficiently and rather selectively perform
fluoroalkylation processes with high yields of target products.
We used this approach to study a possibility of pyrrole
fluoroalkylation under mild conditions taking into account
that pyrrole, as phenols and thiophenols, can form hydroꢀ
gen bonds with bases, although the latter are weaker.20
It was found that under usual conditions pyrrole in
DMSO does not react with Freon BrCF2CF2Br, because
pyrrole cannot reduce Freon or detach from it the posiꢀ
tivated bromine atom. The introduction of various pyꢀ
ridines into the solution enhances the electronꢀdonor abilꢀ
ity of pyrrole. However, this ability is still insufficient for
the spontaneous electron transfer from pyrrole to Freon
and its activation to occur. A different pattern is observed
when sulfur dioxide, viz., an electron transfer mediator, is
added to the system considered. In this case, pyrrole fluoꢀ
roalkylation with the formation of 2ꢀ(2ꢀbromotetraꢀ
fluoroethyl)pyrrole can be performed rather efficiently
(Scheme 1, Table 1).21
The purpose of the present work is to reveal a possibilꢀ
ity of the fluoroalkylation of pyrrole (instead of its salts)
with Freon BrCF2CF2Br by the introduction of the
—
CF2CF2Br group under mild conditions. These objects of
the study were chosen, because pyrrole and its derivatives
find wide use in synthetic practice and the synthesis of its
derivatives containing the —CF2CF2Br group can provide
routes for further modification involving the bromine atom.
We have earlier shown16,17,19 that the fluoroalkylation
with Freons of such organic substrates as thiophenols or
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 564—567, March, 2010.
1066ꢀ5285/10/5903ꢀ0577 © 2010 Springer Science+Business Media, Inc.

578
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
Koshechko et al.
Scheme 1
(2ꢀchloropyridine and 2ꢀacetylpyridine), whereas in the
presence of βꢀpicoline (pKa = 5.97) and 2,5ꢀlutidine
(pKa = 6.25) the process occurs very efficiently, and the
yield of 2ꢀ(2ꢀbromotetrafluoroethyl)pyrrole becomes alꢀ
most quantitative (see Table 2). The results obtained indiꢀ
cate that pyridine with rather high pKa values (5.23 and
higher) should be used for the fluoroalkylation to occur,
and the optimum yields are observed at рКа close to 6. It
should be mentioned that the yield of the target fluoroꢀ
alkylation product decreases and small amounts (8%) of
olefin F2C=CF2 are formed upon the reaction of pyrrole
with Freon in the presence of γꢀcollidine (see Table 2).
This can be associated with the deactivation of the elecꢀ
tron transfer mediator (SO2) due to precipitation in the
presence of γꢀcollidine as a result of the interaction of
sulfur dioxide with collidine. One of the reasons for the
formation of tetrafluoroethylene along with the target fluꢀ
oroalkylation product can be the debromination of Freon
BrCF2CF2Br due to its twoꢀelectron reduction in the pyrꢀ
role—γꢀcollidine—sulfur dioxide system.
As mentioned above, the fluoroalkylation of pyrrole
with Freon BrCF2CF2Br was predetermined by the fact
that the use of a nitrous base—sulfur dioxide system allows
one to activate Freon by the electron transfer from pyrꢀ
role to SO2 and then to Freon to form active radicals
•CF2CF2Br capable of fluoroalkylating pyrrole. To eluciꢀ
date whether the above presented fluoroalkylation process
can proceed via this route and whether sulfur dioxide can
accept an electron from pyrrole and to transfer it to Freon,
we carried out spectrophotometric and electrochemical
studies of particular steps of the process.
Since sulfur dioxide plays the key role in the fluoroꢀ
alkylation of pyrrole with Freon BrCF2CF2Br, we studied
the dependence of the yield of 2ꢀ(2ꢀbromotetrafluoroꢀ
ethyl)pyrrole on the SO2 concentration. It was found that
with an increase in the SO2 concentration the yield of the
fluoroalkylation products increases (see Table 1) and
reaches 85% in experiments with twofold SO2 excess over
the amount of pyrrole taken in the reaction. The yield of
the target fluoroalkylation product decreases with the furꢀ
ther addition of SO2, which can be due to a decrease in the
basicity of the medium with high SO2 concentration.
To reveal the route of the predominant fluoroalkylaꢀ
tion of pyrrole with 1,2ꢀdibromotetrafluoroethane (via the
radical or ionic (halophilic)6,7,19 mechanism), we studied
the influence of traps of free radicals on the yield of fluoꢀ
roalkylation products. It was established that the addition
of a radical trap, in particular, pꢀdinitrobenzene, results in
the complete inhibition of the process, and no products of
pyrrole polyfluoroalkylation are observed (see Table 1),
which indicates the radical route of their formation.
As mentioned above and as follows from the data in
Table 1, the absence of nitrous bases in the solution does
not allow one to obtain target products, which indicates
a significance of the basicity of the medium for the sucꢀ
cessful occurrence of pyrrole fluoroalkylation with
BrCF2CF2Br. Therefore, we studied in more detail the
influence of bases, viz., pyridine with various рKa (the pKa
values concern the conjugated acids of the pyridines studꢀ
ied), on the yields of polyfluoroalkylated pyrroles (Table 2).
We failed to carry out the fluoroalkylation of pyrrole
with Freon BrCF2CF2Br in the presence of weak bases
The electronic absorption spectra of the electrochemiꢀ
–
•
cally generated SO2 radical anion and the products of
its "dimerization" with the initial SO2 have been studied
earlier.22 It was shown that the absorption band with a
–
•
maximum at 485 nm corresponds to the SO2 radical
–
•
anion, and the S2O4 radical anion (λmax = 580 nm)
–
formed by the SO2 • radical anion and the starting sulfur
dioxide is more stable. Taking into account these facts,
Table 1. Dependence of the yield of the product of pyrrole polyꢀ
fluoroalkylation with Freon BrCF2CF2Br, 2ꢀ(2ꢀbromotetraꢀ
fluoroethyl)pyrrole, on the SO2 concentration*
Table 2. Dependence of the yield of the product 2ꢀ(2ꢀbromoꢀ
tetrafluoroethyl)pyrrole on the nature of substituted pyridines*
[SO2]
[βꢀPicoline]
[BrCF2CF2Br]
Yield
of product (%)
10–3 mol
Pyridine
pKa
Yield of product (%)
—
10
10
10
10
10
10
10
—
4.0
4.0
4.0
4.0
4.0
4.0
1.0
4.0
—
2ꢀChloropyridine
2ꢀAcetylpyridine
Pyridine
βꢀPicoline
2,5ꢀLutidine
0.72
3.18
5.23
5.97
6.25
7.60
—
—
78
89
95
62**
0.5
1.0
2.0
4.0
2.0
1.0
1.0
18
51
85
55
—**
78
—
γꢀCollidine
* [Pyrrole] = 0.5•10–3 mol; [SO2] = 0.44•10–3 mol;
[BrCF2CF2Br] = 0.8•10–3 mol; [Substituted pyridine] =
= 1.0•10–2 mol.
* [Pyrrole] = 1•10–3 mol; 25 °C; DMSO.
** The radical trap (pꢀdinitrobenzene) was added.
** In this case, F2C=CF2 (8%) is also found in the products.

Polyfluoroalkylation of pyrrole with Freon
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
579
we studied the electronic absorption spectra of sulfur diꢀ
oxide in DMSO under the following conditions: (1) with
the addition of pyrrole, (2) with the addition of βꢀpicoline
in the absence of pyrrole, and (3) in the presence of pyrꢀ
role and βꢀpicoline. It was found that neither pyrrole, nor
The further development of the process is not evident.
Thus generated bromotetrafluoroethyl radical can furꢀ
ther react with the pyrrole radical cation (its complex
with substituted pyridines), and the subsequent proton
elimination affords 2ꢀ(2ꢀbromotetrafluoroethyl)pyrrole
(Scheme 3).
–
•
βꢀpicoline can reduce SO2 to form the SO2 radical anꢀ
–
ion or its dimeric form S2O4 •. A different situation was
observed when two components (pyrrole and βꢀpicoline)
were simultaneously added to a solution of SO2. In this
case, the solution (in the absence of Freon) turned blue,
and an absorption band with a maximum at 580 nm apꢀ
peared in the electronic spectrum, indicating the formaꢀ
Scheme 3
–
•
tion of the S2O4 radical anion under these conditions.
Thus, as follows from the results of out spectrophotometꢀ
ric studies, sulfur dioxide can withdraw electrons from
pyrrole in the presence of βꢀpicoline. At the same time,
the addition of Freon BrCF2CF2Br to the reaction mixꢀ
ture results in an almost instant disappearance of the blue
color of the solution, which can be due to the interaction
In this process, either the bromide ion, or pyridine can
act as a proton acceptor. It cannot be excluded that the
fluoroalkylation process can proceed via the radical nuꢀ
cleophilic mechanism of the SRN1 type,12,23—25 which
can result in the Cꢀfluoroalkylation of nitrogenꢀcontainꢀ
–
•
of the S2O4 radical anion with Freon. The electronic
absorption spectra of the pyrrole—βꢀpicoline—sulfur diꢀ
–
oxide—Freon system exhibit no SO2 • radical anion or its
12,26
ing heterocycles.
–
•
adduct with SO2—S2O4
.
–
•
The ability of the SO2 radical anion that formed
Experimental
–
(or its adduct S2O4 •) to transfer an electron to Freon
with the regeneration of the starting SO2 and to act thus as
an electron transfer mediator from pyrrole to Freon in the
fluoroalkylation process considered is confirmed by the
results of our voltammetric studies. It was shown16,17 that
considerable catalytic currents caused by the electron
transfer by sulfur dioxide from the cathode to Freon apꢀ
pear during the electrochemical reduction of SO2 in polar
aprotic organic solvents, including DMSO, in the presꢀ
ence of Freon BrCF2CF2Br.
Based on the performed complex of spectrophotometꢀ
ric and electrochemical studies, the initiation of pyrrole
fluoroalkylation with Freon BrCF2CF2Br can be presentꢀ
ed by Scheme 2, where Py is pyridine and its derivatives.
Dimethylformamide was distilled and stored above sieves
1
А4. Pyrrole was distilled prior to use. H and 19F NMR spectra
were recorded on a BrukerꢀCXPꢀ90 spectrometer (relative to
Me4Si and CCl3F, respectively). Electronic spectra were meaꢀ
sured on a Specord Mꢀ10 spectrometer.
A. Reaction of BrCF2CF2Br with pyrrole in the presence of
sulfur dioxide and βꢀpicoline. A solution of sulfur dioxide in DMF
(SO2 = 5•10–4—4•10–3 mol) was added to freshly distilled pyrꢀ
–3
role (0.067 g, 1•10 mol) in DMF or DMSO (0.5 mL) with
βꢀpicoline (0.4 mL, 1•10–2 mol) purged with argon. After addiꢀ
tion of Freon BrCF2CF2Br (0.48 mL, 4•10–3 mol) the total volꢀ
ume of the reaction mixture was brought to 2 mL by DMF. The
mixture was stored in a sealed ampule for 4—6 h at 35 °C, and
then the contents of the ampule was poured into an aqueous
solution of hydrochloric acid (17%), which was extracted with
hexane or chloroform 4—5 times. The organic layer was washed
with water and dried over K2CO3, and the solvent was distilled
off. The residue was distilled in vacuo. 2ꢀ(2ꢀBromotetrafluoroꢀ
ethyl)pyrrole with b.p. 66—68 °С (15 Torr) was obtained.
1H NMR (CDCl3), δ: 6.2 (1 H, H(4)); 6.5 (1 H, H(3)); 7.0 (1 H,
H(5)); 11.9 (1 H, NH). 19F NMR (DMSOꢀd6), δ: 65.7 (t, 2 F,
CF2, J = 5.6 Hz); 102.8 (t, 2 F, CF2, J = 5.6 Hz). Found (%):
C, 29.5; H, 1.7; N, 5.8. C6H4BrF4N. Calculated (%): C, 29.3;
H, 1.6; N, 5.7.
Scheme 2
B. The reaction of BrCF2CF2Br with pyrrole in the presence of
sulfur dioxide and pꢀdinitrobenzene was carried out according to
a procedure similar to procedure A with the addition of pꢀdinitroꢀ
benzene (0.040 g, 0.3•10–3 mol) to the solution.
C. The reaction of BrCF2CF2Br with pyrrole in the presence of
sulfur dioxide and various substituted pyridines was carried out via
a procedure similar to procedure A but with the addition of the
corresponding substituted pyridine instead of βꢀpicoline to
the solution.

580
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
Koshechko et al.
15. X.ꢀT. Huang, Z.ꢀY. Long, Q.ꢀY. Chen, J. Fluor. Chem., 2001,
111, 107.
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in revised form September 11, 2009