Perfluoroalkylation in flow microreactors: Generation of perfluoroalkyllithiums in the presence and absence of electrophiles

Article abstract of DOI:10.1039/c1ob06350b

Perfluoroalkyllithiums were effectively generated from perfluoroalkyl halides in the presence and absence of electrophiles using flow microreactor systems. The in situ trapping with electrophile is conducted at much higher temperatures than those required for batch macro reactors. The subsequent trapping method is quite effective for highly reactive electrophiles that are not compatible with the lithiation process.

Full text of DOI:10.1039/c1ob06350b

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PAPER
Perfluoroalkylation in flow microreactors: generation of
perfluoroalkyllithiums in the presence and absence of electrophiles†
Aiichiro Nagaki,a Shinya Tokuoka,a Shigeyuki Yamada,a Yutaka Tomida,a Kojun Oshiro,b Hideki Amiib and
Jun-ichi Yoshida*a
Received 16th June 2011, Accepted 16th August 2011
DOI: 10.1039/c1ob06350b
Perfluoroalkyllithiums were effectively generated from perfluoroalkyl halides in the presence and
absence of electrophiles using flow microreactor systems. The in situ trapping with electrophile is
conducted at much higher temperatures than those required for batch macro reactors. The subsequent
trapping method is quite effective for highly reactive electrophiles that are not compatible with the
lithiation process.
Introduction
Because long chain perfluoroalkyl groups add unique properties
to parent molecules, perfluoroalkyl-substituted compounds have
received significant research interest from with regard to biological
Scheme 1 The generation of perfluoroalkyllithiums followed by their
reactions with electrophiles and the possibility of b-elimination.
activity and physical functions.1,2 Recently, fluorous chemistry
based on perfluoroalkyl groups serves as a powerful method for
strategic separation because the fluorous phase serves as a new
method for perfluoroalkylation by perfluoroalkyllithiums avoiding
phase that is immiscible to both aqueous and organic phases,
b-elimination is strongly needed.
which is useful for anti-coatings for textiles.3 In this context, there is
Recently, we have reported that flow microreactor systems
a strong demand for synthesizing a variety of organic compounds
are quite effective for controlling reactions involving highly
bearing perfluoroalkyl groups.4 Radical perfluoroalkylation is
unstable reactive intermediates.13 Therefore, we envisaged that
very popular because perfluoroalkyl radicals are easily generated
flow microreactor systems are also effective for the generation and
from readily available precursors, such as perfluoroalkyl halides.5
reactions of fluorine-containing reactive species.14 In this paper,
In contrast, the use of perfluoroalkyl anions has been rather
we show that this is indeed the case. In particular, we report a new
limited because of low nucleophilicity and thermal instability.6
method for conducting anionic perfluoroalkylation involving the
Thermally stable perfluoroalkylmetals, such as perfluoroalkyl
generation of perfluoroalkyllithiums in the absence of electrophiles
zincs and coppers are sometimes not reactive enough toward weak
and subsequent reactions with highly reactive electrophiles that are
electrophiles.7 Perfluoroalkyllithiums, which are often prepared
not compatible with the generation process.
by halogen–lithium exchange reactions of perfluoroalkyl halides
with alkyllithiums are more reactive, but they readily undergo
b-elimination to form perfluoroalkenes (Scheme 1).8 Meanwhile,
flow microreactor methods have received significant interest due
to their prominent abilities of reaction control.9,10,11 Schwalbe
et al. reported that the generation and reaction of pentafluo-
roethyllithium with benzophenone could be performed using a
microreactor but the yield was not high, although the reaction
using a more stable perfluoroethylmagnesium gave high yields.12
With a wide substrate scope, the development of an efficient
Results and discussion
We began with the generation of perfluoroalkyllithiums in the
presence of electrophiles in flow because this method is popular in
batch macro processes.8 Before using a flow microreactor system,
the reaction in a macro batch reactor was examined. A solution of
MeLi (0.42 M in Et2O, 2.25 mL) was added dropwise to a solution
of tridecafluorohexyl iodide (0.10 M) and benzaldehyde (0.12 M)
in Et2O (9 mL) at a particular temperature (T/◦C). After stirring
for 1 min, methanol (neat, 3.0 mL) was added dropwise to this
aDepartment of Synthetic and Biological Chemistry, Graduate School
of Engineering, Kyoto University Nishikyo-ku, 615-8510, Kyoto, Japan.
E-mail:yoshida@sbchem.kyoto-u.ac.jp; Fax: +81-75-383-2725; Tel: +81-
75-383-2726
◦
mixture. After stirring at T C for 10 min, the yield of 1-phenyl-
2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptan-1-ol was determined
by GC (gas chromatography). As shown in Table 1, the reaction
at -78 ◦C gave the product in 67% yield but the reaction at higher
temperatures, such as 0 ◦C, caused a decrease in the yield because
the b-elimination of tridecafluorohexyllithium took place.
bDepartment of Chemistry and Chemical Biology, Graduate School of
Engineering, Gunma University,
† Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/c1ob06350b
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Table 1 The reaction of tridecafluorohexyllithium with benzaldehyde
using a conventional batch macro reactor
Table 2 The reactions of perfluoroalkyllithiums with various electro-
philes
CF3(CF2)nCF2X Electrophile
CF3CF2I
Product
Yield (%)a
84
T/◦C
Yield (%)a
-78
67
46
CF3CF2CF2I
80
85
86
0
CF3(CF2)2CF2I
CF3(CF2)3CF2I
CF3(CF2)4CF2I
a GC yields using an internal standard.
80
(74)b
71
CF3(CF2)4CF2Br
CF3(CF2)4CF2I
Next, a flow microreactor system consisting of two stainless
steel (SUS304) T-shaped micromixers (M1 and M2) and two
stainless steel (SUS316) microtube reactors (R1 and R2) was used
(Fig. 1). The reactions could be cond◦ucted at 0 ◦C, although
much lower temperatures, such as -78 C, are required to avoid
the decomposition of perfluoroalkyllithium intermediates in batch
processes.15 The flow method is applicableto perfluoroalkyliodides
of various chain lengths and various electrophiles, including
aldehydes, ketones and isocyanates (Table 2). It is also noteworthy
that the products were obtained in good yields based on perflu-
oroalkyl halides using 1.2 equiv. of electrophiles, although batch
macro processes are often carried out using an excess amount
of perfluoroalkyl halides and the yields are reported based on
electrophiles.
70
CF3(CF2)4CF2I
CF3(CF2)4CF2I
79
86
CF3(CF2)4CF2I
CF3(CF2)4CF2I
Me3SiOTf
Bu3SnCl
C6F13SiMe3
C6F13SnBu3
30
2
a GC (gas chromatography) yields using an internal standard. b Isolated
yield.
Fig. 1 A flow microreactor system for perfluoroalkylation by the gener-
ation of perfluoroalkyllithiums in the presence of electrophiles. T-shaped
micromixers: M1(250 mm) and M2 (500 mm), microtube reactors: R1 (f =
1000 mm, L = 50 cm) and R2 (f = 1000 mm, L = 50 cm). Flow rate of a
mixture solution of a perfluloroalkyl halide (0.10 M) and an electrophile
(0.12 M) in Et2O: 9.00 mL min-1; flow rate of a solution of MeLi (0.42 M)
in Et2O: 2.25 mL min-1; flow rate of methanol: 3.00 mL min-1.
Fig. 2 A flow microreactor system for perfluoroalkylation by the gener-
ation of perfluoroalkyllithiums in the absence of electrophiles. T-shaped
micromixers: M1(250 mm), M2(250 mm), and M3 (500 mm), microtube
reactors: R1, R2(f = 1000 mm, L = 50 cm), and R3 (f = 1000 mm, L =
50 cm). Flow rate of a solution of a perfluoroalkyl halide (0.10 M) in Et2O:
9.00 mL min-1; flow rate of a solution of MeLi (0.48 M) in Et2O: 2.25 mL
min-1; flow rate of a solution of an electrophile (0.84 M) in Et2O: 1.50 mL
min-1; flow rate of methanol: 2.00 mL min-1.
It should be noted that the use of highly reactive electrophiles,
such as trimethylsilyl triflate and chlorotributylstannane, gave rise
to very low yields of the desired products, which is presumably
because the reactions of MeLi with such electrophiles are faster
than those with perfluoroalkyl halides. To solve this problem,
the generation of a perfluoroalkyllithium and its reaction with
an electrophile should be separated, though it was difficult
or practically impossible to achieve it with a batch macro
reactor because perfluoroalkyllithium undergoes b-elimination
very rapidly. Thus, we examined the use of a flow microreactor
system, because a highly reactive species can be generated and
transferred to another location to be used in the next reaction
before it decomposes by adjusting the residence time from the
millisecond to second time scale. We used a flow microreactor
system consisting of three T-shaped micromixers (M1, M2, and
M3) and three microtube reactors (R1, R2, and R3) shown in
Fig. 2. Tridecafluorohexyl iodide was reacted with MeLi in M1 and
R1 to generate tridecafluorohexyllithium, which was subsequently
reacted with chlorotributylstannane as an electrophile in M2 and
R2. The reaction was carried out varying the temperature (T)
and the residence time in R1 (tR1). As shown in Fig. 3,16 hig◦h yields
(> 80%) were obtained with short tR1, such as 0.15 s at -68 C. The
increase in tR1 caused a decrease in the yield, presumably because
of b-elimination. The present temperature residence time profile is
quite effective to unveil the stability of the perfluoroalkyllithium in-
termediate. In contrast, it is impossible to obtain such information
by the in situ generation–capture method. It is also noteworthy that
the present flow microreactor method has sufficient productivity
for laboratory scale synthesis (477 mg min-1).
◦
Under the optimized conditions (T = -68 C, tR1 = 0.15 s),
the reactions of various perfluoroalkyl halides with highly reac-
tive electrophiles, including chlorotributylstannane, trimethylsilyl
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Experimental
General
GC analysis was performed on a SHIMADZU GC-2014 gas
chromatograph equipped with a flame ionization detector using a
fused silica capillary column (column, CBP1; 0.22 mm ¥ 25 m).
1H NMR spectra were recorded on Varian MERCURYplus-
400 (400 MHz) spectrometer with Me4Si or CDCl3 as a stan-
dard in CDCl3 unless otherwise noted. 13C NMR spectra were
recorded on JEOL ECA-600P (150 MHz) spectrometer with
CDCl3 as a standard in CDCl3 unless otherwise noted. 19F
NMR spectra were recorded on Varian MERCURYplus-400
(377 MHz) spectrometer with trifluorotoluene as a standard
in CDCl3 unless otherwise noted. 119Sn NMR spectrum was
recorded on JEOL ECA-600P (224 MHz) spectrometer with
tetramethyltin as an external standard in CDCl3. EI mass spectra
were recorded on a JMS-SX102A spectrometer. APCI mass
spectra were recorded on an EXACTIVE spectrometer. The
FT-IR spectrum was recorded on a SHIMADZU IRAffinity-1
spectrometer. Gel permeation chromatography (GPC) was carried
out on Japan Analytical Industry LC-908 and LC-9201. Diethyl
ether was purchased from Kanto Chemical Co., Inc. as a dry
solvent and used without further purification. Perfluoroalkyl
halide, benzaldehyde, acetophenone, phenyl isocyanate, n-butyl
isocyanate, chlorotributylstanane, trimethylsilyl triflate, methanol
and MeLi were commercially available. All solutions used for
flow reactions were prepared under an argon atmosphere using
dry solvents. Stainless steel (SUS304) T-shaped micromixers with
inner diameters of 250 and 500 mm were manufactured by Sanko
Seiki Co., Inc. Stainless steel (SUS316) microtube reactors with an
inner diameter of 1000 mm was purchased from GL Sciences. The
micromixer and microtube reactors were connected with stainless
steel fittings (GL Sciences, 1/16 OUW). The microflow system was
dipped in a cooling bath to control the temperature. Solutions were
introduced to the flow microreactor system using syringe pumps,
Harvard Model 11, equipped with gastight syringes purchased
from SGE.
Fig. 3 Effects of the temperature (T) and the residence time (tR1) on the
yield of tridecafluorohexylstannane for the reaction of tridecafluorohexyl
iodide with MeLi to generate tridecafluorohexyl–lithium followed by the
reaction with chlorotributylstannane using the flow microreactor system.
Contour plot with scatter overlay of the yields of tridecafluorohexylstan-
nane (%), which are indicated by numbered circles.
trifrate and isocyanates, were successfully carried out to obtain the
desired products in good yields (Table 3).
Conclusions
In conclusion, we developed an efficient method for perfluo-
roalkylation using perfluoroalkyllithium intermediates. The in situ
generation–capture method can be achieved without using an
excess of perfluoroalkyl halides at much higher temperatures,
such as 0 ◦C, than those required for batch macro processes.
Moreover, the generation of perfluoroalkyllithium in the absence
of electrophiles followed by the reaction with subsequently
added eletrophiles was also achieved because b-elimination can
be avoided by virtue of a short residence time and efficient
temperature control in the flow microreactor system. Therefore,
the present two methods greatly enhance the synthetic utility of
perfluoroalkyllithium intermediates and add a new dimension to
the synthesis of organofluorine compounds.
Typical procedure for the generation of perfluoroalkyllithiums in
the presence of electrophiles in the flow microreactor system
Table 3 The reactions of perfluoroalkyllithiums with various electro-
philes
A flow microreactor system consisting of two T-shaped micromix-
ers (M1 and M2), two microtube reactors (R1 and R2) and three
tube pre-cooling units (P1 (inner diameter f = 1000 mm, length L =
150 cm), P2 (f = 1000 mm, L = 50 cm) and P3 (f = 1000 mm, L =
50 cm)) was used. A mixing solution of CF3(CF2)nCF2X (0.10 M
in Et2O) and an electrophile (0.12 M in Et2O) (flow rate: 9.0 mL
min-1) and a solution of MeLi (0.42 M in Et2O) (flow rate: 2.25 mL
min-1) were introduced to M1 (f = 250 mm) by syringe pumps. The
resulting solution was passed through R1 (f = 1000 mm, L = 50 cm)
and was mixed with methanol (neat) (flow rate: 3.0 mL min-1) in
M2 (f = 500 mm). The resulting solution was passed through R2
(f = 1000 mm, L = 50 cm). After a steady state was reached, an
aliquot of the product solution was collected for 30 s and was
treated with sat. aqueous NH4Cl solution. The reaction mixture
was analyzed by GC using an internal standard.
Yield
CF3(CF2)nCF2X Electrophile
Product
(%)a
CF3CF2I
Bu3SnCl
CnF2n+1SnBu3 (n = 2, 3, 4, 5, 6) 98
CF3 CF2CF2I
CF3(CF2)2CF2I
CF3(CF2)3CF2I
CF3(CF2)4CF2I
CF3(CF2)4CF2Br
CF3(CF2)4CF2I Me3SiOTf
CF3(CF2)4CF2I
81
84
90
87
75
82
87
C6F13SiMe3
CF3(CF2)4CF2I
91
1-Phenyl-2,2,3,3,3-pentafluoropropan-1-ol. Obtained in 84%
yield (GC tR 11.6 min). The spectral data were identical to those
reported in the literature.4c
a GC yields using an internal standard.
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1-Phenyl-2,2,3,3,4,4,4-heptafluorobutan-1-ol. Obtained
in
Tri-n-butyl(1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexyl)-stan-
nane. Obtained in 2% yield (GC tR 19.9 min). The spectral data
were identical to those reported in the literature.19
t
80% yield (GC R 12.4 min). The spectral data were identical to
those reported in the literature.17
1-Phenyl-2,2,3,3,4,4,5,5,5-nonafluoropentan-1-ol. Obtained in
85% yield (GC tR 13/4 min). The spectral data were identical to
those reported in the literature.17
Typical procedure for the generation of perfluoroalkyllithiums in
the absence of electrophiles in the flow microreactor system
A flow microreactor system consisting of three T-shaped mi-
cromixers (M1, M2 and M3), three microtube reactors (R1, R2
and R3), and four tube pre-cooling units (P1(inner diameter f =
1000 mm, length L = 150 cm), P2 (f = 1000 mm, L = 50 cm) and P3
(f = 1000 mm, L = 50 cm), P4 (f = 1000 mm, L = 50 cm)) was used.
A solution of perfluoroalkyl halide (0.10 M in Et2O) (flow rate:
9.0 mL min-1) and a solution of MeLi (0.48 M in Et2O) (flow rate:
2.25 mL min-1) were introduced to M1 (f = 250 mm) by syringe
pumps. The resulting solution was passed through R1 and was
mixed with a solution of an electrophile (0.84 M in Et2O) (flow
rate: 1.5 mL min-1) in M2 (f = 250 mm). The resulting solution was
passed through R2 (f = 1000 mm, L = 50 cm) and was quenched by
mixing with methanol (flow rate: 2.0 mL min-1) in M3 (f = 500 mm).
The resulting solution was passed through R3 (f = 1000 mm, L =
50 cm). After a steady state was reached, an aliquot of the product
solution was collected for 30 s and was treated with sat. aqueous
NaHCO3 solution. The reaction mixture was analyzed by GC
using an internal standard.
1-Phenyl-2,2,3,3,4,4,5,5,6,6,6-undecafluorohexan-1-ol.
Obtained in 86% yield (GC tR 14.3 min). After extraction,
the crude product was purified by column chromatography
(hexane/ethyl acetate = 20/1 to 10/1): 1H NMR (400 MHz,
CDCl3) d 2.51 (d, J = 5.2 Hz, 1H), 5.22 (dt, J = 5.6 Hz, J = 17.6
Hz, 1H), 7.41–7.49 (m, 5H); 13C NMR (150 MHz, CDCl3) d 72.3
(dd, J = 23.0 Hz, J = 28.0 Hz), 106.2–107.4 (m), 108.0–115.4 (m),
116.2–117.1 (m), 118.3 (t, J = 33.0 Hz), 120.3 (t, J = 33.0 Hz),
128.1, 128.6, 129.7, 134.0; 19F NMR (377 MHz, CDCl3) d -81.2
(t, J = 10.2 Hz, 3F), -118.0–(-127.6) (m, 8F); HRMS (APCI) m/z
calcd for C12H7F11OCl ([M+Cl]-): 411.0004, found: 441.0014.
1-Phenyl-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptan-1-ol.
Obtained in 80% yield (GC tR 15.2 min). The spectral data were
identical to those reported in the literature.17
1-Methyl-1-phenyl-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptan-
1-ol. Obtained in 70% yield (GC tR 15.5 min). The spectral data
were identical to those reported in the literature.18
Tri-n-butyl(1,1,2,2,2-pentafluroroethyl)stannane. Obtained in
98% yield (GC R 18.0 min). The spectral data were identical
to those commercially available sample.
2,2,3,3,4,4,5,5,6,6,7,7,7-Tridecafluoro-N-phenylheptanamide.
Obtained in 79% yield (GC tR 16.1 min). After extraction,
the crude product was purified by column chromatography
(hexane/ethyl acetate = 5/1):1H NMR (400 MHz, CDCl3) d
7.24–7.28 (m, 1H), 7.38–7.43 (m, 2H), d 7.55–7.58 (m, 2H),
7.15–7.22 (m, 3H), 7.91 (brs, 1H); 13C NMR (150 MHz, DMSO)
d 105.5–112.7 (m), 113.8 (t, J = 33.0 Hz), 115.7 (t, J = 33.0 Hz),
117.6 (t, J = 33.0 Hz), 119.5 (t, J = 33.0 Hz), 121.3, 125.7, 128.7,
136,3, 155.1 (t, J = 25.8 Hz); 19F NMR (377 MHz, DMSO) d -82.3
(t, J = 10.2 MHz, 3F), -120.0–(-127.8) (m, 10F); HRMS (EI)
m/z calcd for C13H6ONF13 (M+): 439.0242, found: 270.439.0233.
t
Tri-n-butyl(1,1,2,2,3,3,3-heptafluoroopropyl)stannane.
t
Obtained in 70% yield (GC R 18.2 min). The spectral data
were identical to those reported in the literature.20
Tri-n-butyl(1,1,2,2,3,3,4,4,4-nonafluorobutyl)stannane.
t
Obtained in 84% yield (GC R 18.7 min). The spectral data
were identical to those reported in the literature.[20]
Tri-n-butyl(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyl)stannane.
t
Obtained in 90% yield (GC R 19.2 min). After extraction, the
2,2,3,3,4,4,5,5,6,6,7,7,7-Tridecafluoro-N-n-butylheptanamide.
Obtained in 86% yield (GC tR 12.5 min). After extraction,
the crude product was purified by column chromatography
(hexane/ethyl acetate = 10/1 to 5/1): 1H NMR (400 MHz,
CDCl3) d 0.94 (t, J = 7.2 Hz, 3H), 1.32–1.42 (m, 2H), d1.53–1.61
crude product was purified by GPC:1H NMR (400 MHz, CDCl3)
d 0.30 (s, 9H), 0.92 (t, J = 7.4 Hz, 3H), 1.10–1.39 (m, 4H),
1.46–1.67 (m, 2H); 13C NMR (150 MHz, CDCl3) d 10.7, 13.4,
27.3, 28.5, 106.4–107.6 (m), 108.2–115.1 (m), 116.8 (t, J = 33.0
Hz), 118.7 (t, J = 33.0 Hz), 120.6 (t, J = 33.0 Hz), 127.7–133.2
(m); 19F NMR (377 MHz, CDCl3) d -81.3 (t, J = 10.2 Hz, 3F),
-117.8–(-126.8) (m, 8F); 119Sn NMR (224 MHz, CDCl3) d 0.51 (t,
J = 191 Hz); HRMS (EI) m/z calcd for C13H18F11Sn ([M-Bu]+):
503.0255, found: 503.0254.
(m, 2H), 3.39 (dt, J = 6.4 Hz, J = 6.4 Hz, 3H), 6.30 (brs, 1H); 13
C
NMR (150 MHz, CDCl3) d 13.1, 19.8, 30.8, 40.0, 106.2–113.2
(m), 114.4 (t, J = 33.0 Hz), 116.3 (t, J = 33.0 Hz), 118,2 (t, J =
33.0 Hz), 120.1 (t, J = 33.0 Hz), 158.1 (t, J = 25.9 Hz); 19F NMR
(377 MHz, CDCl3) d -81.2 (t, J = 10.2 Hz, 3F), 120.1–(-236.7)
(m, 10F); HRMS (APCI) m/z calcd for C11H11NOF13 ([MH]+):
420.0628, found: 420.0618.
Notes and references
Trimethyl(1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexyl)silane.
Obtained in 30% yield (GC R 4.3 min). After extraction, the
1 (a) T. Hiyama, K. Kanie, T. Kusumoto, Y. Morizawa and M. Shimizu,
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t
crude product was purified by GPC: 1H NMR (400 MHz, CDCl3)
d 0.30 (s, 9H); 13C NMR (150 MHz, CDCl3) d -4.8, 106.5–107.8
(m), 108.3–114.1 (m), 114.6–115.6 (m), 116.7 (t, J = 33.0 Hz),
118.6 (t, J = 33.0 Hz), 120.5 (t, J = 33.0 Hz), 121.6 (t, J = 44.5
Hz), 123.4 (t, J = 44.5 Hz), 125.2 (t, J = 46.0 Hz); 19F NMR (377
MHz, CDCl3) d -81.3 (t, J = 10.2 Hz, 3F), -119.4–(-128.9) (m,
10F).
3 J. A. Gladysz, D. P. Curran and I. T. Horva´th,Handbook of Fluorous
Chemistry, Wiley-VCH, Weinheim, 2004.
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4 Recent examples of perfluoroalkylation: (a) C. Pooput, W. R. Dolbier
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