Synthesis of perfluoroalkyl-substituted aryl bromides and their purification over fluorous reverse phase silica

Article abstract of DOI:10.1055/s-1998-2186

(1H,1H,2H,2H-Perfluoroooctyl)-substituted aryl bromides 3a,b were synthesized via copper catalyzed cross-coupling of the iodide 1 with the corresponding arylmagnesium bromides 2a,b. A new, efficient method for the purification of highly fluorinated compounds by column chromatography on fluorous reverse phase silica is also described.

Full text of DOI:10.1055/s-1998-2186

October 1998
SYNTHESIS
1425
Synthesis of Perfluoroalkyl-Substituted Aryl Bromides and Their Purification Over
Fluorous Reverse Phase Silica
a
b
b
a
Sabine Kainz, Zhiyong Luo, Dennis P. Curran,* Walter Leitner*
a
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)306 2993; E-mail: leitner@mpi-muelheim.mpg.de
Department of Chemistry, Chevron Science Center, 219 Parkman Avenue, Pittsburgh, PA 15260, USA
b
Fax +1(412)624 9861; E-mail: curran+@pitt.edu
Received 29 April 1998
Abstract: (1H,1H,2H,2H-Perfluoroooctyl)-substituted aryl bro-
mides 3a,b were synthesized via copper catalyzed cross-coupling
of the iodide 1 with the corresponding arylmagnesium bromides
ties of the substituted aryl group. As a first demonstration
of this approach, we have recently synthesized ortho-, me-
ta- and para-(1H,1H,2H,2H-perfluorooctyl)-substituted
aryl phosphines starting from compounds of type 3;2a
these phosphines were successfully applied as ligands in
the rhodium-catalyzed hydroformylation of higher olefins
in scCO2.2 Related phosphines lacking the spacer have
been synthesized for FBS applications by other groups.4
2
a,b. A new, efficient method for the purification of highly fluori-
nated compounds by column chromatography on fluorous reverse
phase silica is also described.
Key words: perfluorinated compounds, copper-catalyzed C–C
coupling, fluorous reverse phase silica, catalysis, ligands
a,b
Compounds containing highly fluorinated chains We now report details on the synthesis of two representa-
(CH ) (CF ) F are receiving great current interest as tive examples of (1H,1H,2H,2H-perfluorooctyl)-substi-
–
2
z
2 y
stoichiometric reagents and as catalysts for selective chem- tuted aryl bromides, 3a,b, via copper catalyzed cross-cou-
ical transformations. The unique solubility properties of pling of the iodide 1 with the corresponding arylmagne-
highly fluorinated compounds open possibilities to apply sium bromides 2a,b. A new, efficient method for the
these materials to organic syntheses in innovative reaction purification of highly fluorinated compounds by column
1
media like “fluorous biphasic systems” (FBS) or in super- chromatography on fluorous reverse phase silica is also
2
critical carbon dioxide (scCO ). Likewise, highly fluori- described. The preparative separation of fluorinated from
2
nated reagents, reactants and substrates are also useful for non-fluorinated compounds by fluorous reverse phase
5
synthesis in traditional solvents, because they can readily silica gel has recently been introduced, and this is the first
3
be separated from non-fluorinated compounds. These po- application of separation of fluorinated compounds from
tential practical applications lead to a considerable and ever each other based on the number of fluorines contained.
increasing demand for readily accessible and versatile
The mono-Grignard reagents 2a,b are readily available by
building blocks containing perfluoroalkyl chains at the end
of short alkylene (typically ethylene) spacers.
reaction of the corresponding dibromobenzenes with ex-
6
cess magnesium turnings in refluxing Et O in high yields.
2
In this context, aryl bromides of type 3 are of special Not surprisingly, direct treatment of 4-BrC H MgBr (2b)
6
4
interest because they allow the introduction of with 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-iodooctane
(
1H,1H,2H,2H-perfluorooctyl)-substituted aryl groups (1, 1H,1H,2H,2H-perfluorooctyl iodide) did not result in
like [Ar(CH ) (CF ) F] into a wide variety of target mol- formation of the corresponding cross-coupled product 3b.
2
2
2 6
ecules via well-established transformations of the reactive However, 3b was obtained in fair to good yield when cata-
aryl–bromide bond. The ethylene spacer effectively lytic amounts of Cu(I) were introduced in form of
blocks the strong electron-withdrawing effect of the long [(cod)CuCl] (cod = 1,5-cyclooctadiene).7
perfluoroalkyl chain from the aromatic ring in 3a,b and
The catalytic activity of Cu(I) compounds for cross-cou-
potential derivatives thereof. The variable substitution
pling reactions of Grignard reagents with alkyl halides is
pattern of commercially available dibromobenzenes
should result in a systematic variation of the steric proper-
8
well-established and has been independently applied by
9
Shimizu et al. for similar reactions. In the present case,
addition of diethyl ether solutions of the Grignard re-
agents 2a,b to a slurry of the Cu(I) complex in THF con-
taining 1 at temperatures below 0°C and subsequent
warming of the resulting mixtures to room temperature
gave optimum results. The crude products obtained after
aqueous workup contained the desired compounds 3a,b
together with small amounts of bromobenzene resulting
from hydrolysis of unreacted 2 and the symmetrical ho-
modimer 1,4-bis(perfluorohexyl)butane (4) as the major
side products.
Isolation of analytically pure (1H,1H,2H,2H-perfluorooct-
yl)aryl bromides from the crude materials obtained by the

1
426
Short Papers
SYNTHESIS
above procedure proved to be a key problem limiting the lyzed Grignard reaction. The desired products 3a and 3b
use of 3a,b as synthetic building blocks. Attempts to sep- were very difficult to separate from the homocoupling
arate 3 and 4 by flash chromatography on silica gel or by product 4 by flash chromatography or distillation, but
crystallization from various solvents failed owing to the were readily separated by filtration over fluorous reverse
similar polarity and solubility behavior of these com- phase silica. The aryl bromides 3a and 3b are generally
pounds. Distillation under reduced pressure gave main useful fluorinated components for making ligands, re-
fractions (50–60% of the crude product) containing 3a,b agents and catalysts, and separations over fluorous reverse
with GC purities ~90%. Further purification to yield ana- phase silica may frequently prove to be the methods of
lytically pure samples of 3a,b was possible by preparative choice in preparing other highly fluorinated compounds.
GC, if desired. NMR spectroscopic data and elemental
analyses suggested that the actual content of 3a,b in the
All reactions involving air- or moisture-sensitive materials were per-
main fractions of distillation was somewhat higher than
formed under argon using standard Schlenk techniques in dried and
oxygen-free solvents. 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-io-
dooctane (1, 1H,1H,2H,2H-perfluorooctyl iodide) as well as m- and
p-dibromobenzene were commercial products (Clariant, Aldrich) and
used as received. FC-72 is a trademark of the 3M corporation and is
mostly perfluorohexanes.
1
0
indicated by GC and the material proved sufficiently
2
a
pure for most preparative purposes. Nevertheless, the
wasteful and time-consuming distillation procedure is not
fully satisfactory from a practical and analytical point of
view. In our search for further improvement, we found
that chromatography with fluorous reverse phase silica
gel offers significant advantages over conventional tech-
niques. This methodology allows rapid and quantitative
purification of crude 3a,b with potential for applications
on a synthetically useful scale.
NMR spectra were recorded in 5 mm tubes on a Bruker AC 200 and
1
13
AM 200 spectrometer operating at 200.1 and 50.3 for H and C and
on a Bruker AMX 300 spectrometer operating at 282.4 MHz for 19F.
1
Chemical shifts are reported in ppm relative to external TMS for H
and 13C and CFCl for F, using the solvent resonance as a secondary
19
3
standard if possible. Coupling constants J are given in Hz. The assign-
ments of ambiguous signals in the aromatic region are based on the
increment method.12 Multiplets marked with a star (e.g. d*) are part
of higher order spin systems which were not fully analyzed.
MS were measured on a Finnigan MAT 8200 with EI technique. GC-
MS-coupling was performed on a Finnigan MAT SSQ with EI tech-
nique. GC analyses were carried out on a Carlo Erba 4100 EIS chro-
matograph (column: 30 m, 100% methylpolysiloxan, inner diameter:
0.25 mm, coat thickness: 0.25 µm, detector: FID, temp: 6°C/min in-
jector: 220°C, oven: 60–330°C, 6/min, 10 min isotherm, detector:
We have recently introduced the new technique of fluor-
ous solid phase extraction for the separation of fluorous
(
highly fluorinated) compounds from organic com-
5
pounds. Fluorous reverse phase (FRP) silica gel is pre-
pared by silylation of standard silica gel with
ClSi(Me )CH CH C F . This FRP silica has a low affin-
2
2
2 6 13
ity for organic compounds compared to fluorous com-
pounds. As an extension of this approach, it seems proba-
ble that differentially fluorinated compounds will be re-
tained differently on FRP silica: highly fluorinated
compounds will be more strongly retained while mole-
cules with fewer fluorines will be more weakly retained.11
320°C, gas: 0.6 bar H ). The given GC-purities are taken from the
2
10
integrated peak areas without corrections. Purification by prepara-
tive GC was carried out on a Perkin–Elmer F21 chromatograph (col-
umn: 4.5 m, 8 mm, 20% SE-54 on volaspher A4, 100–120 mesh, col-
umn temp: 160°C, flow: 120 mL/min N ). Elemental analyses were
2
carried out in the microanalytical laboratory Dornis & Kolbe, Mül-
heim a. d. Ruhr.
Dimer 4 contains two 1H,1H,2H,2H-perfluorooctyl
chains while 3a and 3b contain only one chain with a sub-
stantive organic part. Thus, we hypothesized that the re-
tention of 3a and 3b on FRP silica would be weaker than
that of dimer 4. To test this notion, a mixture of 3b (~75%)
and 4 (~25%) obtained by fractional distillation was
charged onto a short column packed with FRP silica. Elu-
tion with acetonitrile and evaporation provided pure 3b.
Washing the column with diethyl ether in turn gave pure
1-Bromo-3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)benzene
(3a):
A solution of m-dibromobenzene (38.1 g, 0.16 mol) in Et O (50 mL)
2
was added dropwise under stirring to Mg turnings (4.31 g, 0.18 mol)
in Et O (20 mL). The rate of addition was adjusted to maintain the
2
solution under gentle reflux. The resulting mixture was stirred for 3 d
at r.t. and then filtrated to give a greenish ethereal solution of 2a
(
1.9 M, 87%).13 Part of this solution (55.1 mL, 104.7 mmol 2a) was
added to a suspension of 1 (45.1 g, 95.0 mmol) and [(cod)CuCl] (ca.
00 mg) in THF (40 mL) at –3°C. The mixture was allowed to warm
4. Thus, both compounds can be recovered quantitatively
3
in a process that resembles a solid phase extraction more
than a chromatography, and expensive fluorocarbon sol-
vents are not needed. In small trial experiments, we found
that using about ten times weight of FRP silica compared
to the weight of the mixture of 3b and 4 was satisfactory;
reducing the amount of silica by half overloaded the col-
umn. Assorted distillation fractions containing 50–90%
to r.t. under stirring overnight. Hydrolysis and extraction with Et O
2
gave 44.8 g of a red oil which was distilled over a Vigreux column (19
cm, 16 mm) to give 24.3 g of a colorless oil at a boiling point of 95–
100°C (10–2 Torr). This material contained 89% 3a according to GC
analysis (21.6 g, 45%). An analytically pure sample of 3a was ob-
tained by preparative GC.
1
H NMR (200 MHz, CDCl , 27°C): δ = 7.10–7.66 (m, 4H; HC2,
3
HC4, HC5, HC6), 2.94 (m, 2H; H C1), 2.41 (m, 2H; H C2).
2
2
3b were separated by this method to give individual, pure
13
1
C{ H} NMR (50.3 MHz, CDCl , 27°C): δ = 141.5 (s; C3), 122.8 (s;
3
products. Similarly, a mixture of 3a and 4 was also sepa-
rated with FRP silica. After use, the fluorous FRP silica
was washed and dried prior to repeated reuse.
C1), 131.5 (s; HC2), 130.3 (s; HC5), 130.0 (s; HC6), 127.0 (s; HC4),
3
2
26.2 (t, J = 4.4 Hz; H C1), 32.8 (t, J = 22.7 Hz; H C2), 105.0–
FC
2
FC
2
125.0 (6 signals, m; F C3–F C8).
F{ H} NMR (282.4 MHz, CDCl , 29°C): δ = –81.9 (t, 3F, J = 4
2
3
19
1
3
3
FF
In summary, (1H,1H,2H,2H-perfluorooctyl)-substituted
aryl bromides 3a and 3b were synthesized via Cu(I) cata-
Hz; F C8), –127.0 (br, 2F; F C7), –124.3 (br, 2F; F C6), –123.7 (br,
3
2
2
3
2F; F C5), –122.7 (br, 2F; F C4), –115.4 (t, 2F, J = 4 Hz; F C3).
2
2
FF
2

October 1998
MS (70 eV, EI): m/z (%) = 502 (100) [M ], 423 (25) [M – ( Br)],
SYNTHESIS
1427
+
+
79
W.L. wishes to thank the Max-Planck-Gesellschaft, the Deutsche For-
schungsgemeinschaft (Gerhard-Hess-Programm) and the Fonds der
Chemischen Industrie for financial support and Clariant GmbH,
Werk Gendorf, for generous donation of chemicals. D.P.C. thanks the
National Institute of Health for support.
+
1
69 (85) [M – CH C F ].
2 6 13
Anal. C H BrF (503.10) calcd C, 33.42; H, 1.60; Br, 15.88; F,
1
4
8
13
4
9.09. Found C, 33.59; H, 1.71; Br, 15.68; F, 49.17.
1
-Bromo-4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)benzene
(
3b):
(1) Horváth, I. T.; Rábai, J. Science 1994, 266, 72.
A solution of p-dibromobenzene (236 g, 0.97 mol) in Et O (ca.
2
Cornils, B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2057.
2) (a) Kainz, S.; Koch, D.; Baumann, W.; Leitner, W. Angew.
Chem. 1997, 109, 1699; Angew. Chem., Int. Ed. Engl. 1997, 36,
4
1
50 mL) was added dropwise under stirring to Mg turnings (25.5 g,
(
.05 mol) in Et O (60 mL). The rate of addition was adjusted to main-
2
tain the solution under gentle reflux. The resulting mixture was stirred
1628.
overnight at r.t. and then filtrated to give a brownish ethereal solution
of 2b (1.92 M, 100%).13 Part of this solution (520 mL, 0.97 mol 2b)
(b) Koch, D.; Leitner, W. J. Am. Chem. Soc. submitted for
publication.
was added to a suspension of 1 (477 g, 0.97 mmol) and [(cod)CuCl]
(c) Hadida, S.; Super, M. S.; Beckman, E. J.; Curran, D. P.
(ca. 1.6 g) in THF (640 mL) at –20°C. The mixture was warmed to
J. Am. Chem. Soc. 1997, 119, 7406.
r.t. under stirring over a period of 4 h. Hydrolysis and extraction with
Et O yielded 478 g of a brown oil which was distilled over a Vigreux
(
3) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531.
Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823.
2
column (19 cm, 16 mm) to give two colorless main fractions: the first
fraction (119 g) was collected between 78–80°C/10– Torr and con-
2
Hoshino, M.; Degenkolb, P.; Curran, D. P. J. Org. Chem. 1997,
62, 8341.
Curran, D. P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1174.
tained 90% 3b according to GC analysis. The second fraction (116 g)
collected at temperatures of 80–93°C/10– Torr was analytically pure.
2
The total isolated yield of preparatively useful 3b was 223 g (46%).
1
(4) Bhattacharyya, P.; Gudmunsen, D.; Hope, E. G.; Kemmitt, R.
H NMR (200 MHz, CDCl , 27°C): δ = 7.33 (d*, 2H, J = 8.4 Hz;
3
D. W.; Paige, D. R.; Stuart, A. M. J. Chem. Soc., Perkin Trans.
HC2, HC6), 6.97 (d*, 2H, J = 8.4 Hz; HC3, HC5), 2.77 (m, 2H;
H C1), 2.24 (m, 2H; H C ).
1
1997, 3609.
2
2 2
13
1
Betzemeier, B.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1997,
36, 2623.
C{ H} NMR (50.3 MHz, CDCl , 27°C): δ = 138.2 (s; C4), 120.7 (s;
3
3
C1), 130.0 (s; HC3, HC5), 132.0 (s; HC2, HC6), 26.0 (t, J
=
FC
2
(5) Curran, D. P.; Hadida, S.; Mu, H. J. Org. Chem. 1997, 62, 6714.
6) Staab, H.; Binnig, F. Chem. Ber. 1967, 100, 293.
4
.4 Hz; H C1), 32.8 (t, J = 22.2 Hz; H C2), 105.0 – 128.0 (6 sig-
2
FC
2
(
nals, m; F C3 – F C8).
2
3
19
1
3
Gomberg, S. A. M.; Baillar, J. C. J. Am. Chem. Soc. 1929, 51,
F{ H} NMR (282.4 MHz, CDCl , 29°C): δ = –81.9 (t, 3F, J
=
3
FF
2232.
8
.5 Hz; F C8), –127.1 (br, 2F; F C7), –124.3 (br, 2F; F C6), –123.7
3 2 2
Ziegler, K.; Tiemann, P. Chem. Ber. 1922, 55, 3414.
(br, 2F; F C5), –122.7 (br, 2F; F C4), –115.4 (br, 2F; F C3).
2 2 2
+
+
(7) Kainz, S. Diploma Thesis, MPI für Kohlenforschung/Universi-
tät Duisburg, 1996; we thank Prof. Dr. G. Dyker for the possi-
bility to conduct an external Diploma thesis.
8) Tamura, M.; Kochi, J. Synthesis 1971, 303.
Tamura, M.; Kochi, J. J. Organomet. Chem. 1972, 42, 205.
March, J. In Advanced Organic Chemistry, 3rd ed.; Wiley: New
York, 1985; p 402.
GC-MS-coupling (70 eV, EI): m/z (%): = 502 (55) [M ], 423 (15) [M
–
Anal. C H BrF (503.10) calcd C, 33.42; H, 1.60; Br, 15.88; F,
79
+
( Br)], 169 (100) [M – CH C F ].
2 6 13
1
4
8
13
(
4
9.09. Found C, 33.55; H, 1.70; Br, 15.97; F, 48.69.
Preparation of Fluorous Reverse Phase Silica:5
Flash chromatography grade silica (ICN silicaTech 32-63 D 60 A)
was dried at 120°C under high vacuum overnight. The dried silica gel
(
9) Shimizu, R.; Yoneda, E.; Fuchikami, T. Tetrahedron Lett. 1996,
37, 5557.
(30.0 g) was heated at 100°C in dry toluene (80 mL) containing imi-
(
10) GC analyses are given as the integrated peak areas without cor-
rections. We note, however, that perfluorinated compounds
tend to give very low response in FID detection and exact quan-
tification requires calibration.
dazole (9.5 g) and ClSi(Me) CH CH C F (50.0 g) for 3 d without
stirring. The resulting silica gel was washed sequentially with tolu-
ene, MeOH, MeOH/H O, THF, Et O, and MeCN before drying under
2
2
2 6 13
2
2
high vacuum to yield fluorous reverse phase silica gel (47.8 g).
(
11) Billiet, H. A. H.; Schoenmakers, P. J.; De Galan, L. J. Chromat.
1
981, 218, 443.
Varughese, P.; Gangoda, M. E.; Gilpin, R. K. J. Chromat. Sci.
988, 26, 401.
Danielson, N. D.; Beaver, L. G.; Wangsa, J. J. Chromat. 1991,
44, 187.
Purification of 3a and 3b Over Fluorous Reverse Phase Silica:
A short column packed with FRP silica (3.66 g) was wetted with Et O
2
1
before washing with MeCN. To this column, a 3:1 mixture (NMR
integration) of 3b and 4 (350 mg) was loaded. The column was first
eluted with MeCN (8 mL) to give pure 3b (244 mg). Pure 4 (97 mg)
5
(
12) Hesse, M.; Meier, H.; Zeeh, B. In Spektroskopische Methoden
in der Organischen Chemie, 2nd ed.; Thieme Verlag: Stuttgart,
was washed out with Et O (16 mL): total recovery, 97%. Resonances
2
1
for 3b could not be detected in the H NMR spectrum of the Et O
2
1
984.
13) Gilman, H.; Zoellner, E. A.; Dickey, J. B. J. Am. Chem. Soc.
929, 51, 1576.
fraction while resonances for 4 could not be detected in the spectrum
of the MeCN fraction. Similarly, a 1:1 mixture (NMR integration) of
(
1
3
a and 4 (33 mg) was separated with FRP silica (330 mg) by eluting
with MeCN (2 mL) and FC-72 (1 mL) successively to give pure 3a
13 mg) and pure 4 (18 mg): total recovery, 94%. The FRP silica was
recovered after washing with acetone, MeCN, Et O, hexanes and FC-
(
2
7
2.