Fluorination with XeF2. 44. Effect of geometry and heteroatom on the regioselectivity of fluorine introduction into an aromatic ring

Full text of DOI:10.1021/jo971496e

878
J . Org. Chem. 1998, 63, 878-880
F lu or in a tion w ith XeF 2.1 44. Effect of
Geom etr y a n d Heter oa tom on th e
Regioselectivity of F lu or in e In tr od u ction
in to a n Ar om a tic Rin g
tions of the effect of geometry, electronegativity of sub-
stituent, and strain on the type of transformation. These
reactions involve regioselectivity at the aromatic ring or
side chain functionalization with various reagents (bro-
mination, nitration, chlorination, alkylation, acylation,
and anodic and photochemical cyanation). Electrophilic
substitution in fluorene occurs mainly at the 2 and 4
positions; however, the regioselectivity of functionaliza-
tion of DBF depends on the reagent used. Bromination20
and acylation21,22 occurred mainly at position 2, function-
alization at position 3 was more pronounced in anodic
and photochemical cyanation,23 but nitration strongly
Marko Zupan,* J ernej Iskra, and Stojan Stavber
Laboratory of Organic and Bioorganic Chemistry, Faculty
of Chemistry and Chemical Technology, and J . Stefan
Institute, University of Ljubljana,
Asˇkercˇeva 5, 1000 Ljubljana, Slovenia
Received August 12, 1997
depends on the reagent used (93% at position 3 in
99%HNO3/TFA22 and 52% at position 2 in a NaNO3, N3
,
-
In tr od u ction
AcOH/H2SO4 mixture24). Ionic attack was suggested to
explain predominant substitution at position 2, and ion
radicals were proposed as intermediates for 3-substituted
products, while radical attack resulted in almost equal
amount of four products.23
Direct introduction of fluorine under mild reaction
conditions into aromatic molecules is still only a partly
solved problem, particularly if the aromatic ring is not
activated.2-6 Xenon difluoride is one of the oldest re-
agents used for aromatic ring functionalization, and
substitution,7-10 addition,11-14 and in some cases side
chain fluorination10,15 were observed. It is evident that
even a small structural variation in the organic substrate
could completely change the course of fluorination, and
the important role of solvent polarity and catalyst (HF,
BF3, BF3‚OEt2, C6F5SH, TFA, TFA-Ag+, etc.) has also
been pointed out.2a,4-6
To obtain further information of the role of the struc-
ture of the aromatic molecule on the type of fluorine atom
introduction, we found it instructive to study the reac-
tions of fluorene (1a ), DBF (1b), and structurally related
biphenyl (5a ), diphenylmethane (4b), and diphenylether
(5c) with XeF2.
Resu lts a n d Discu ssion
Fluorene (1a ) and dibenzofuran (DBF, 1b) have been
used several times16-19 as target molecules in investiga-
First we investigated the regioselectivity of room-
temperature fluorination of fluorene 1a using XeF2
catalyzed with BF3‚OEt2. In a typical experiment 0.5
mmol of 1a was dissolved at room temperature in 5 mL
of CH2Cl2, 0.5 mmol of XeF2 was added, and the reaction
was catalyzed with a drop of BF3‚OEt2 solution. The
reaction mixture immediately turned dark blue, and
xenon gas was evolved. After being stirred for 3 h, the
reaction mixture was isolated and the crude reaction
(1) For part 43, see: Stavber, S.; Koren, Z.; Zupan, M. Synlett 1994,
265.
(2) (a) German, L.; Zemskov, S. New Fluorinating Agents in Organic
Synthesis; Springer-Verlag: Berlin, 1989. (b) Hudlicky, M.; Pavlath,
A. E., Eds. Chemistry of Organo Fluorine Compounds II; ACS
Monograph 187; American Chemical Society: Washington, DC, 1996.
(c) Clark, J . H.; Wails, D.; Bastock, T. W. Aromatic Fluorinations; CRC
Press: New York, 1996.
(3) Patai, S.; Rappoport, Z., Eds.; The Chemistry of Functional
Groups, Supplement D2: The Chemistry of Halides, Psevdo-Halides
and Azides, Part 1 and Part 2; Wiley: Chichester, 1995.
(4) Zupan, M. Xenon Halide Halogenations, In The Chemistry of
Functional Groups, Supplement D: The Chemistry of Halides, Pseudo-
Halides and Azides; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester,
1983.
(5) Zupan, M. Functionalization of Organic Molecules by Xenon
Fluorides. In The Chemistry of Functional Groups, Supplement D2:
The Chemistry of Halides, Psevdo-Halides and Azides; Patai, S.,
Rappoport, Z., Eds.; Wiley: Chichester, 1995.
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Soc. 1970, 92, 5096.
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1
product analyzed by H and 19F NMR spectroscopy and
gas chromatography. The crude reaction mixture showed
only two signals in its 19F NMR spectrum (-116.2 ppm
(ddd) and -120.8 ppm (ddd) in 2:1 ratio) indicating only
ring fluorination, and no evidence for side chain fluorina-
tion of the methylene carbon was found. The major
product was assigned as 2-fluorofluorene (4a ) and the
minor one as 4-fluorofluorene (2a ), while the crude
reaction mixture contained only 30% of fluorinated
products (as determined by 19F NMR with octafluo-
ronaphthalene as internal standard). The regioselectiv-
ity of fluorene fluorination with XeF2 was similar to that
of nitration in acetic anhydride25 at -43 °C (67% at C2
and 33% at C4); however, higher regioselectivity was
observed in bromination, where 97% of 2-bromofluorene
was formed.26 The regioselectivity was explained by a
(13) Stavber, S., Zupan, M. J . Org. Chem. 1981, 46, 300.
(14) Frohn, H. J .; Bardin, V. V. J . Chem. Soc., Chem. Commun.
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ester, 1990.
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Y.; Kitajima, H. Chem. Lett. 1988, 1285.
(17) Sargent, M. V.; Stransky, P. O. Dibenzofurans. In Advances in
Heterocyclic Chemistry, Vol. 35; Katritzky, A. R., Ed.; Academic
Press: Orlando, 1984.
(18) Traven, V. F. Frontier Orbitals and Properties of Organic
Molecules; Ellis Horwood: New York, 1992.
(22) Keumi, T.; Tomioka, N.; Hamanaka, K.; Kakihara, H.; Fuku-
shima, M.; Morita, T.; Kitajima, H. J . Org. Chem. 1991, 56, 4671.
(23) Eberson, L.; Radner, F. Acta Chem. Scand. 1992, 46, 312.
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B. O. Acta Chem. Scand. 1993, 47, 176.
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Theoretically Interesting Molecules, Vol. 3; J AI Press Inc.: Greenwich,
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S0022-3263(97)01496-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/13/1998

Notes
J . Org. Chem., Vol. 63, No. 3, 1998 879
Ta ble 1. Effect of Rea gen t Str u ctu r e on th e
Regioselectivity of Diben zofu r a n (1b) F u n ction a liza tion
Sch em e 1
larger coefficient of electron density at C2 (0.390) than
at C4 (0.278) in its HOMO established by MNDO calcu-
lation.25 On the other hand, the regioselectivity of
fluorine introduction was lower than that in the case of
indan,19 where only â-attack was observed in fluorination
with XeF2.9
acetonitrile at 70 °C (entry 4). From the table it is
apparent that the regioselectivity of DBF ring function-
alization strongly depends on the reagent structure. It
is evident that free radical attack gave almost equimolar
amounts of four products (entry 10), ionic attack gave
mainly 2-substituted product (entries 12 and 13), and the
higher amount of the 3-substituted derivative observed
in alkylation (entry 11) was explained by a difference in
the relative stability of the σ-complex intermediate22 (late
transition state). Almost exclusive formation of 3-sub-
stituted product in nitration in TFA (entry 7) was
explained by the formation of an ion radical, and a similar
predominance of attack at position 3 was also observed
in reaction of an ion radical generated either electro-
chemically (entry 8) or photochemically (entry 9).
Finally we studied the regioselectivity of fluorine
introduction into structurally related biphenyl (5a ),
diphenylmethane (5b), and diphenyl ether (5c). Func-
tionalization of biphenyl (5a ) also depends on the reagent
used, and fluorination with XeF2 (Scheme 1) is very
similar to nitration, where ortho attack is predominant29
(p:o is 0.46). On the other hand, in bromination para
attack prevailed.30 In the reaction of XeF2 with diphe-
nylmethane (5b), para attack slightly prevailed (no
fluorination in the meta position or the methylene was
detected) and a regioselectivity similar to that for nitra-
tion in acetic anhydride at room temperature31 (p:o ) 1.2)
was observed, while in chlorination with molecular
chlorine a higher proportion of ortho attack was ob-
served32 (p:o ) 0.86). Substitution of the CH2 group by
oxygen (5c) increased the para regioselectivity in diphe-
nyl ether fluorination (p:o ) 1.6) (Scheme 1), nitration
was less regioselective31 (p:o ) 1.0), and again very high
predominance of para attack was observed in bromina-
tion.33
It has been demonstrated that dibenzofuran (1b) is an
interesting model compound in which ionic attack oc-
curred predominantly at position 2, while functionaliza-
tion at position 3 was ascribed to the formation of an ion
radical intermediate. Calculated HOMO electron densi-
ties for DBF are on the order22 of 0.301 for 3, 0.125 for 1,
0.061 for 2 and 0.041 for 4. On the other hand, the
relative energies (kcal/mol) of protonated dibenzofurans
are in the following order:22 0.0 for 2 > 0.69 for 4 > 3.05
for 3 > 3.23 for 1. Recently it has been demonstrated
that various substituted dibenzofurans could be con-
verted to ion radicals, and their structures were con-
firmed by EPR spectroscopy27 (the spectrum observed in
the oxidation of DBF, however, corresponds to the an-
thracene ion radical). Normalization of theoretical spin
densities over positions 1 to 4 in the DBF radical cation
gave the following distributions for the 2A2 state:27
2
1-18%, 2-6%, 3-59%, and 4-16% and for the B1 state
1-12%, 2-37%, 3-17%, and 4-32%. The experimen-
tally established spin density distribution was as
follows:27 1-25%, 2-1%, 3-67%, and 4-7%. XeF2
reacted with DBF (1b) in CH2Cl2 at room temperature
without a catalyst, but the yield of fluorinated products
could be enhanced with BF3‚OEt2 as catalyst (from 17%
to 30%). The crude reaction mixture showed three major
signals at -113.7 ppm (ddd), -118.8 ppm (ddd), and
-121.0 ppm (ddd) and one minor one at -137.0 ppm
(ddd). The three major products were isolated by pre-
parative TLC and GLC, and on the basis of their
spectroscopic data and comparison with literature data
and independently prepared samples, they were identi-
fied as 1-fluorodibenzofuran (2b), 2-fluorodibenzofuran
(3b) and 3-fluorodibenzofuran (4b). As is evident from
Table 1 the presence of BF3‚OEt2 increased fluorine
attack at position 3 (entries 2 and 3), and the regiose-
lectivity was also different (attack at positions 2 and 3)
from that observed in fluorination with F-TEDA28 in
Similarity in the regioselectivity of the dibenzofuran
(1a ) toward nitration,22 anodic and photochemical cya-
nation,23 and XeF2 functionalization suggests that the
formation of an ion radical intermediate is the most
probable intermediate. Free radical type of functional-
(29) Mizuno, Y.; Simamura, O. J . Chem. Soc. 1958, 3875.
(30) Berliner, E.; Powers, J . C. J . Am. Chem. Soc. 1961, 83, 905.
(31) Dewar, M. J . S.; Urch, D. S. J . Chem. Soc. 1958, 3079.
(32) de la Mare, P. B. D.; J ohnson, E. A.; Lomas, J . S. J . Chem. Soc.
1965, 6893.
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C. J . J . Chem. Soc., Perkin Trans. 2 1996, 1289.
(28) Zupan, M.; Iskra, J .; Stavber, S. Tetrahedron 1996, 52, 11341.
(33) Seshadri, K. V.; Ganesan, R. Tetrahedron 1972, 28, 3827.

880 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
copy with octafluoronaphthalene as internal reference and
calculated on the basis of starting substrate. Complete exclusion
of ambient light had no effect on the conversion and product
distribution. Products were isolated by preparative TLC or GC,
and the structure was determined on the basis of spectroscopic
data and by comparison with commercial samples, literature
data, or independently prepared samples.
F lu or in a tion of F lu or en e (1a ). The crude reaction mixture
(77 mg) was isolated containing 30% of fluorinated products
(ratio of 2a :4a ) 1:2): 4-fluorofluorene42 (2a ), δF ) -120.8 ppm
(m); 2-fluorofluorene42 (4a ), δF ) -116.2 ppm (ddd).
F lu or in a tion of Bip h en yl (5a ). The crude reaction mixture
(79 mg) was isolated containing 46% of fluorinated products
(ratio of 6a :7a ) 1:0.9): 2-fluorobiphenyl43 (6a ), δF ) -116.0
ppm (m); 4-fluorobiphenyl43 (7a ), δF ) -118.2 ppm (m).
F lu or in a tion of Dip h en ylm eth a n e (5b). The crude reac-
tion mixture (80 mg) was isolated containing 20% of fluorinated
products (ratio of 6b:7b ) 1:1.2): 2-fluorodiphenylmethane44
(6b ), δF ) -118.5 ppm (m); 4-fluorodiphenymethane45 (7b ),
δF ) -117.7 ppm (dd).
F lu or in a tion of Dip h en yl Eth er (5c). The crude reaction
mixture (87 mg) was isolated containing 44% of fluorinated
products (ratio of 6c:7c ) 1:1.6): 2-fluorodiphenyl ether46 (6c),
δF ) -130.5 ppm (m); 4-fluorodiphenyl ether46 (7c), δF ) -120.0
ppm (dd).
F lu or in a tion of Diben zofu r a n (1b). The crude reaction
mixture (89 mg) was isolated containing 30% of fluorinated
products (ratio of 2b:3b:4b ) 1:1:2): 1-fluorodibenzofuran28 (2b),
δF -118.8 ppm (ddd, J ) 12, 6, 1 Hz); 2-fluorodibenzofuran47
(3b), δF ) -121.0 ppm (ddd, J ) 9, 5 Hz); 3-fluorodibenzofuran47
(4b), δF ) -113.7 ppm (ddd, J ) 9, 5 Hz).
ization is less probable due to the absence of fluorine
attack at position 4, which is characteristic of radical
attack, as in photochemically initiated cyanation23 with
ICN where almost equal amounts of four substituted
products were observed (Table 1, entry 10). Nitration of
monosubstituted aromatic molecules has been exten-
sively studied, and the formation of ion radicals as
intermediates has been suggested.34-40 Similarity in the
regioselectivity of nitration and XeF2 functionalization
of studied aromatic molecules supported the formation
of ion radicals, which were also observed in the fluorina-
tion of some aromatic molecules.7,8
Exp er im en ta l Section
Fluorene (J anssen Chimica), 2-fluorofluorene (Fluorochem
Limited), biphenyl (Fluka), diphenymethane (Fluka), diphenyl
ether (Fluka), dibenzofuran (Matheson Coleman), BF3‚OEt2
(Merck), and octafluoronaphthalene (Fluorochem) were obtained
from commercial sources. XeF2 was prepared by photosynthetic
methods,41 and its purity was better than 99.5%. Acetonitrile
(Merck) and methylene chloride (Merck) were purified by
distillation and stored over molecular sieves. 1H and 19F NMR
spectra were recorded by a Varian EM360L spectrometer at 60
or 56.45 MHz with Me4Si or CCl3F as internal standards, gas
chromatography was carried out on Varian Models 3700 and
3300, and TLC was carried out on Merck PSC-Fertigplatten
silica gel F-254.
F lu or in a tion w ith XeF 2. In 25 mL plastic bottle was
dissolved 0.5 mmol of substrate (1a , 1b, 5a , 5b, 5c) in 5 mL of
CH2Cl2. The 0.5 mmol of XeF2 was added and the reaction
catalyzed with a drop of BF3‚OEt2. After being stirred for 3 h
at room temperature, the reaction mixture was diluted with 25
mL of CH2Cl2, washed with water (10 mL) and a saturated
solution of NaHCO3 (10 mL), and dried over Na2SO4 and the
solvent was removed under reduced pressure. Yields of fluori-
nated products were determined by 1H and 19F NMR spectros-
Ack n ow led gm en t. The financial support of the
Ministry of Science and Technology of the Republic of
Slovenia is acknowledged.
J O971496E
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