Practical synthesis of photochromic diarylethenes in integrated flow microreactor systems

Article abstract of DOI:10.1002/cssc.201100376

An effective method for the synthesis of photochromic diarylethenes through the generation of heteroaryllithiums and subsequent reaction with octafluorocyclopentene has been developed by using integrated flow microreactor systems. Reactions can be conducted without using cryogenic conditions by virtue of effective temperature and residence time control, although much lower temperatures (<-78°C) are needed for batch macroreactions. Moreover, the synthesis of unsymmetrical diarylethenes, which is difficult to achieve when using conventional batch macrosystems, has been accomplished based on the selective introduction of one aryl group to give arylheptafluorocyclopentene followed by the introduction of another aryl group. The productivity of the laboratory-scale system is approximately 0.5 mmolmin^-1. Therefore, the present integrated flow microreactor method serves as a practical way of synthesizing various photochromic diarylethene derivatives. Too successful to be cool: An effective method for the synthesis of photochromic diarylethenes has been developed by using integrated flow microreactor systems. Reactions can be conducted without the need for cryogenic conditions by using these systems (see picture). The synthesis of unsymmetrical diarylethenes, which is difficult to achieve by using conventional macro batch systems, has also been accomplished. Copyright

Full text of DOI:10.1002/cssc.201100376

DOI: 10.1002/cssc.201100376
Practical Synthesis of Photochromic Diarylethenes in
Integrated Flow Microreactor Systems
Tatsuro Asai,[a] Atsushi Takata,[b] Aiichiro Nagaki,[c] and Jun-ichi Yoshida*[c]
An effective method for the synthesis of photochromic diaryl-
ethenes through the generation of heteroaryllithiums and sub-
sequent reaction with octafluorocyclopentene has been devel-
oped by using integrated flow microreactor systems. Reactions
can be conducted without using cryogenic conditions by
virtue of effective temperature and residence time control, al-
though much lower temperatures (<À788C) are needed for
batch macroreactions. Moreover, the synthesis of unsymmetri-
cal diarylethenes, which is difficult to achieve when using con-
ventional batch macrosystems, has been accomplished based
on the selective introduction of one aryl group to give arylhep-
tafluorocyclopentene followed by the introduction of another
aryl group. The productivity of the laboratory-scale system is
approximately 0.5 mmolminÀ1. Therefore, the present integrat-
ed flow microreactor method serves as a practical way of syn-
thesizing various photochromic diarylethene derivatives.
Introduction
Various types of photochromic compounds have been synthe-
sized in an attempt to apply them in photonic devices, such as
high-density optical recording materials and photoswitches.[1]
Among various thermally irreversible photochromic com-
pounds, diarylethene derivatives, including diarylhexafluorocy-
clopentenes, are the most promising candidates because some
of them exhibit remarkable color changes through reversible
switching of two distinct isomers, which is accomplished by
absorption of different colors of light, as exemplified in
Scheme 1.[2,3]
Scheme 2. Synthesis of photochromic diarylethenes. a) Generation of hetero-
aryllithiums through the Br/Li exchange reaction of heteroaryl bromides and
b) the reaction of octafluorocyclopentene with heteroaryllithium.
dustry.[7,8] Recent investigations revealed significant features of
flow microreactor systems, such as fast mixing, which stems
from short diffusion paths, and fast heat transfer by virtue of
high surface-to-volume ratios; these features are advantageous
to increase the selectivity of chemical reactions. Short resi-
dence times in a microchannel are beneficial for controlling
Scheme 1. Photochromism of diarylethenes. X=Y=S, O; R1–R6 =alkyl, aryl
Photochromic diarylethene derivatives with heteroaryl
groups, such as thiophene, thiazole, benzothiophene, benzo-
furan, and indole rings, have been synthesized previously.[4] In
general, the synthesis consists of the generation of heteroaryl-
lithium compounds by the halogen–lithium exchange reaction
of heteroaryl halides and subsequent treatment with octafluor-
ocyclopentene. The reaction in a conventional batch macro-
reactor should be performed at low temperatures, such as
À788C or below, because heteroaryllithium compounds are
often unstable and decompose at higher temperatures
(Scheme 2).[5,6] The requirement for such low temperatures,
however, has been an obstacle to industrial-scale production.
Chemical synthesis in flow microreactor systems has re-
ceived significant research interest from both academia and in-
[a] T. Asai
The Research Association of Micro Chemical
Process Technology (MCPT) in Kyoto
Kyoto University, Kyoto, 615-8530 (Japan)
[b] A. Takata
Yamada Chemical Co., Ltd.
Minami-ku, Kyoto, 601-8105 (Japan)
[c] Dr. A. Nagaki, Prof. Dr. J.-i. Yoshida
Department of Synthetic and Biological Chemistry
Graduate School of Engineering
Kyoto University, Nishikyo-ku, Kyoto, 615-8510 (Japan)
Fax: (+81)75-383-2727
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100376.
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J.-i. Yoshida et al.
highly reactive intermediates. By taking advantage of such fea-
tures of flow microreactor systems, various chemical reactions
for organic synthesis have been developed.[9] Flow microreac-
tors are also effective for the integration of reactions to en-
hance the power of organic synthesis.[10] Recently, we reported
that the generation of highly reactive aryllithium compounds,
based on a halogen–lithium exchange reaction and subse-
quent reactions with electrophiles, could be conducted in inte-
grated flow microreactor systems.[9r,s,11] This finding prompted
us to study the generation of heteroaryllithium compounds
and reactions with octafluorocyclopentene in an integrated
flow microreactor system. In a preliminary communication, we
reported that heteroaryllithium compounds were generated
and used for reactions with octafluorocyclopentene in a con-
trolled way by using flow microreactors.[12] We also reported
the preliminary result that undesired ring opening of some
heteroaryllithium compounds could be suppressed by temper-
ature–residence time control in flow microreactors.[13] Based on
these studies, we have developed practical methods for the
synthesis of symmetrical and unsymmetrical diarylethenes with
thiophene, thiazole, benzothiophene, and benzofuran rings by
fully optimizing the reaction conditions for both steps. Herein,
we report the full details of this study.
two microtube reactors (R1 and R2), shown in Figure 1a, to op-
timize the reaction conditions for the generation of heteroaryl-
lithium compounds. We also constructed an integrated flow
microreactor system that consisted of three T-shaped micro-
mixers (M1, M2, and M3) and three microtube reactors (R1, R2,
and R3), shown in Figure 1b, to synthesize symmetrical diaryl-
ethanes. By using this system, the conditions for the reaction
of heteroaryllithium compounds with octafluorocyclopentene
were optimized.
Br/Li exchange reaction of 1a followed by reaction with octa-
fluorocyclopentene
First, we chose to study the synthesis of a photochromic, sym-
metrical diarylethene with two thiophene units [1,2-bis(2-
methyl-5-phenyl-3-thienyl)perfluorocyclopentene (4aa)], which
could be prepared from the Br/Li exchange reaction of 3-
bromo-2-methyl-5-phenylthiophene (1a) and a subsequent
twofold addition–elimination reaction with octafluorocyclopen-
tene (Scheme 3).[14]
The reaction conditions for the Br/Li exchange of 1a to give
(2-methyl-5-phenylthiophen-3-yl)lithium (2a), which is the first
step of the desired transformation, were optimized by using
the flow microreactor system shown in Figure 1a. A solution of
1a (0.10m in THF; flow rate: 6.0 mLminÀ1) and a solution of n-
Results and Discussion
butyllithium (nBuLi; 0.42m in hexane; flow rate: 1.5 mLminÀ1
)
were introduced into M1 (f=500 mm) by using syringe
pumps. The resulting solution was passed through R1 and was
mixed with a solution of iodomethane (0.60m in hexane; flow
rate: 3.0 mLminÀ1) in M2 (f=500 mm). The resulting solution
was passed through R2 (f=1000 mm, L=50 cm). After a
steady state was reached, the resulting solution was collected
Synthesis of symmetrical diarylethenes
The first step of the synthesis of diarylethenes is the halogen–
lithium exchange reaction of heteroaryl halides with butyllithi-
um. In the next step, the heteroaryllithium compounds are al-
lowed to react with octafluorocyclopentene. Usually, two
moles of
a
heteroaryllithium
compound react with one mole
of octafluorocyclopentene pre-
sumably through a twofold addi-
tion–elimination sequence to
give the corresponding symmet-
rical diarylethenes. We construct-
ed a flow microreactor system
that consisted of two T-shaped
micromixers (M1 and M2) and
Scheme 3. Br/Li exchange reaction of 1a with nBuLi and subsequent twofold addition–elimination reaction with
octafluorocyclopentene.
Figure 1. Flow microreactor syntheses of photochromic symmetrical diarylethenes. a) A flow microreactor system for the Br/Li exchange reaction of heteroaryl
halides with nBuLi followed by reaction with an electrophile (E; methanol or iodomethane), and b) an integrated flow microreactor system for the Br/Li ex-
change reaction of heteroaryl halides with nBuLi followed by the reaction with octafluorocyclopentene (micromixers: M1, M2, and M3; microtube reactors:
R1, R2, and R3).
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Synthesis of Photochromic Diarylethenes
for 30 s. The conversion of 1a and the yield of 2,3-dimethyl-5-
phenylthiophene were determined by using GC. The reaction
temperature (T) was controlled by adjusting the bath tempera-
ture. The residence time in R1 (tR1) was varied by changing the
length of R1 while maintaining a fixed flow rate. The results
obtained with varying tR1 and T are profiled in Figure 2. The
conversion and the yield significantly depended on both tR1
at the same temperature (T). The residence time in R2 (tR2) was
varied by changing the length of R2 while maintaining a fixed
flow rate. The results obtained by varying tR2 and T are profiled
in Figure 3.
Figure 3. Temperature–residence time (in R2) map for the Br/Li exchange re-
action of 1a with nBuLi followed by the reaction with octafluorocyclopen-
tene in an integrated flow microreactor system. Contour plot with scatter
overlay of the yield of 1,2-bis(2-methyl-5-phenyl-3-thienyl)perfluorocyclopen-
tene (4aa) indicated by numbered circles.
Figure 2. Temperature–residence time (in R1) map for the Br/Li exchange re-
action of 1a with nBuLi followed by reaction with iodomethane in a flow
microreactor system. a) Contour plot with scatter overlay of the conversion
of 1a and b) contour plot with scatter overlay of the yield of 2,3-dimethyl-5-
phenylthiophene; conversion and yield indicated by numbered circles.
The yield of 4aa significantly depended on both T and tR2.
The yield increased with T and tR2 because of the progress of
the reaction. It should be noted that high yields (>90%) were
obtained even at 0 or 248C, which demonstrated that the use
of the integrated flow microreactor system enabled the syn-
thesis of photochromic diarylethenes without using cryogenic
conditions. In other words, this reaction can be inherently con-
ducted at 0 and 248C. The reaction in batch macroreactors suf-
fers from the problem of insufficient heat removal, and there-
fore, overcooling is necessary. In addition, the productivity of
the present system is reasonable for laboratory-scale syntheses
(7.31 ghÀ1).
and T. In the low temperature (T<08C)–short residence time
(tR1 <0.1 s) region, the starting material remained unchanged
to some extent because the Br/Li exchange reaction was
rather slow at low temperatures (Figure 2a). Conversely, the
yield of 2,3-dimethyl-5-phenylthiophene was high in the high
temperature (T>À288C)–long residence time (tR1 >1 s) region.
Notably, the reaction can be conducted even at 08C; this
demonstrates a significant advantage of the flow microreactor
systems.[8a,11c,15]
Using this result, we next examined the reaction of 2a with
octafluorocyclopentene, which is the second step of the de-
sired transformation, by using the integrated flow microreactor
system shown in Figure 1b. A solution of 1a (0.10m in THF;
flow rate: 6.0 mLminÀ1) and a solution of nBuLi (0.42m in
hexane; flow rate: 1.5 mLminÀ1) were introduced into M1 (f=
500 mm) by using syringe pumps. The resulting solution was
passed through R1 with the optimized residence time [tR1 =
0.22 (T=24), 1.6 (0), 1.6 (À28), 6.3 s (À488C)]. The resulting so-
lution of 2a was mixed with a solution of octafluorocyclopen-
tene (0.13m in THF; flow rate: 2.0 mLminÀ1) in M2 (f=
500 mm), was passed through
Br/Li exchange reaction of 1b followed by reaction with octa-
fluorocyclopentene
Next, we studied the synthesis of symmetrical 4bb.[4e,16] For
this purpose, 3-bromo-2,4-dimethyl-5-phenylthiophene (1b)
was used as a starting material (Scheme 4).
The Br/Li exchange reaction of 1b to generate (2,4-dimeth-
yl-5-phenylthiophen-3-yl)lithium (2b) was performed by using
the flow microreactor system shown in Figure 1a. A solution of
R2, and was mixed with metha-
nol (flow rate: 3.0 mLminÀ1) in
M3 (f=500 mm), which would
quench unchanged lithium spe-
cies very quickly. The resulting
solution was passed through R3
(f=1000 mm, L=50 cm). The
generation of 2a and the subse-
Scheme 4. Br/Li exchange reaction of 1b with nBuLi and subsequent twofold addition–elimination reaction with
quent reaction were conducted octafluorocyclopentene.
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J.-i. Yoshida et al.
1b (0.10m in THF; flow rate: 6.0 mLminÀ1) and a solution of
nBuLi (0.42m in hexane; flow rate: 1.5 mLminÀ1) were intro-
duced into M1 (f=500 mm) by using syringe pumps. The reac-
tion mixture was passed through R1 and was quenched with
methanol (neat; flow rate: 3.0 mLminÀ1) in M2 (f=500 mm)
and R2. The results obtained by varying tR1 and T are profiled
in Figure 4. We found that the reaction could be conducted
Figure 5. Temperature–residence time (in R2) map for the Br/Li exchange re-
action of 1b with nBuLi followed by the reaction with octafluorocyclopen-
tene in an integrated flow microreactor system. Contour plot with scatter
overlay of the yield of 1,2-bis(2,4-dimethyl-5-phenyl-3-thienyl)perfluorocyclo-
pentene (4bb) indicated by numbered circles.
the absorption spectra.[19] Symmetrical dithiazolylhexafluorocy-
clopentene could be synthesized through the Br/Li exchange
reaction of 4-bromo-5-methyl-2-phenylthiazole (1c) followed
by reaction with octafluorocyclopentene (Scheme 5). The con-
ditions for the Br/Li exchange reaction of 1c was optimized by
using the flow microreactor system shown in Figure 1a. A solu-
Figure 4. Temperature–residence time (in R1) map for Br/Li exchange reac-
tion of 1b with nBuLi followed by the reaction with methanol in a flow mi-
croreactor system. a) Contour plot with scatter overlay of the conversion of
1b and b) contour plot with scatter overlay of the yield of 2,4-dimethyl-5-
phenylthiophene; conversion and yield indicated by numbered circles.
even at 08C. Interestingly, the
Br/Li exchange reaction of 1b
was slower than that of 1a
when comparing Figures 2a and
4a. This is presumably because
of the electron-donating effect
Scheme 5. Br/Li exchange reaction of 1c with nBuLi and the subsequent twofold addition–elimination reaction
with octafluorocyclopentene.
of the methyl group. Therefore,
the present method (quench-
flow method[17]) serves as a pow-
erful tool for mechanistic studies on extremely fast reactions.
By using the optimized conditions for the Br/Li exchange re-
action of 1b [tR1 =0.79 (T=24), 0.79 (0), 1.6 (À28), 6.3 s
(À488C)], the subsequent reaction with octafluorocyclopen-
tene was investigated by using the integrated flow microreac-
tor system shown in Figure 1b. The yield of 4bb significantly
depended on both temperature (T) and residence time in R2
(tR2), and the synthesis of 4bb could be effectively performed
even at 08C (Figure 5). Remarkably, the addition–elimination
reaction of 2b with octafluorocyclopentene was slower than
that of 2a, presumably because of steric hindrance (Figure 3
vs. 5). The productivity of the present system is reasonable for
large-scale syntheses (6.42 ghÀ1).
tion of 1c (0.10m in THF; flow rate: 6.0 mLminÀ1) and a solu-
tion of nBuLi (0.42m in hexane; flow rate: 1.5 mLminÀ1) were
introduced into M1 (f=500 mm) by using syringe pumps. The
resulting solution was passed through R1 and mixed with
methanol (neat; flow rate: 3.0 mLminÀ1) in M2 (f=500 mm).
The results obtained by varying tR1 and T are visualized in
Figure 6 and show that the reaction could be performed even
at 0 and 248C.
By using the optimized conditions for the Br/Li exchange re-
action of 1c [tR1 =0.79 (T=24), 0.79 (0), 3.1 (À28), 3.1 s
(À488C)], the subsequent reaction with octafluorocyclopen-
tene was investigated by using the integrated flow microreac-
tor system shown in Figure 1b. As shown in Figure 7, the reac-
tion could be conducted even at 248C, although the yield of
1,2-bis(5-methyl-2-phenyl-4-thiazolyl)perfluorocyclopentene
(4cc) significantly depended on both T and tR2. The yield of
4cc increases with an increase in tR2, indicating that the reac-
tion of 2c with octafluorocyclopentene was slower than that
of 2a and 2b (Figure 3 vs. 5 vs. 7). The productivity of 4cc was
5.46 ghÀ1 under the optimized conditions.
Br/Li exchange reaction of 1c followed by reaction with octa-
fluorocyclopentene
Thiazole and thiophene are isoelectronic, and dithiazolyl-
hexafluorocyclopenenes also exhibit thermally irreversible
photochromic reactions.[18] Irie et al. have reported that the
substitution position on the thiazole rings strongly affected
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Synthesis of Photochromic Diarylethenes
The conditions of the Br/Li exchange reaction of 1d were
optimized by using the flow microreactor system shown in Fig-
ure 1a.
A solution of 1d (0.10m in THF; flow rate:
6.0 mLminÀ1) and a solution of nBuLi (0.42m in hexane; flow
rate: 1.5 mLminÀ1) were introduced into M1 (f=500 mm) by
using syringe pumps. The resulting solution was passed
through R1 and mixed with a solution of iodomethane (flow
rate: 3.0 mLminÀ1) in M2 (f=500 mm). In Figure 8a, the con-
Figure 6. Temperature–residence time (in R1) map for the Br/Li exchange re-
action of 1c with nBuLi followed by the reaction with methanol in a flow
microreactor system. a) Contour plot with scatter overlay of the conversion
of 1c and b) contour plot with scatter overlay of the yield of 5-methyl-2-
phenylthiazole; conversion and yield indicated by numbered circles.
Figure 8. Temperature–residence time (in R1) map for the Br/Li exchange re-
action of 1d with nBuLi followed by the reaction with iodomethane. a) Con-
tour plot with scatter overlay of the conversion of 1d, b) contour plot with
scatter overlay of the yield of 2,3-dimethylbenzothiophene, and c) contour
plot with scatter overlay of the yield of 1-methylsulfanyl-2-(prop-1-ynyl)ben-
zene; conversion and yields indicated by numbered circles.
Figure 7. Temperature–residence time (in R2) map for the Br/Li exchange re-
action of 1c with nBuLi followed by the reaction with octafluorocyclopen-
tene in an integrated flow microreactor system. Contour plot with scatter
overlay of the yield of 4cc indicated by numbered circles.
version of 1d is plotted against the temperature (T) and the
residence time in R1 (tR1) as a contour map with scattered
overlay. In the low temperature (T<08C)–short residence time
(tR1 <0.1 s) region, compound 1d remained unchanged to
some extent because the Br/Li exchange reaction was rather
slow at low temperatures. In Figure 8b, the yields of the me-
thylated product 2,3-dimethylbenzothiophene are plotted
against T and tR1. High yields were obtained with long resi-
dence times at low temperatures (such as tR1 >1.0 s, T<
À288C). The increase in temperature caused a decrease in the
yield presumably because of the ring-opening reaction of in-
termediate 2d (Scheme 7). In the higher temperature region
(T>08C), the product derived from ring opening, 1-methylsul-
fanyl-2-(prop-1-ynyl)benzene, was obtained in good yields (Fig-
ure 8c). The reaction pathways
Br/Li exchange reaction of 1d followed by reaction with octa-
fluorocyclopentene
Benzothiophene provides a fatigue-resistant property to a di-
arylethene in solution, and benzothiophene-containing diaryl-
ethenes are photochemically inactive in the crystalline
phase.[4b,20] Therefore, we next synthesized the symmetrical dia-
rylethene with benzothiophene units by the Br/Li exchange of
3-bromo-2-methybenzothiophene (1d) followed by reaction
with octafluorocyclopentene (Scheme 6).
could be controlled by choosing
appropriate temperatures and
residence times. For example,
2,3-dimethylbenzothiophene,
the product derived from ben-
zo[b]thiophen-3-yllithium
(2d)
without ring opening, was ob-
tained in 86% yield at tR1 =1.6 s
and T=À488C, whereas 1-meth-
Scheme 6. Br/Li exchange reaction of 1d with nBuLi and subsequent twofold addition–elimination reaction with
octafluorocyclopentene.
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J.-i. Yoshida et al.
3-bromo-2-methylbenzofuran (1e) followed by the reaction
with octafluorocyclopentene (Scheme 8).
The conditions for the Br/Li exchange of 1e was optimized
by using the flow microreactor system shown in Figure 1a.
A solution of 1e (0.10m in THF; flow rate: 6.0 mLminÀ1) and a
solution of nBuLi (0.42m in hexane; flow rate: 1.5 mLminÀ1
)
were introduced to M1 (f=500 mm) by using syringe pumps.
The resulting solution was passed through R1 and mixed with
a solution of methanol (neat; flow rate: 3.0 mLminÀ1) in M2
(f=500 mm). The results obtained by varying tR1 and T are pro-
filed in Figure 10. Figure 10a (conversion) indicates that the
Scheme 7. Control of ring-opening reaction of 2d and benzo[b]furan-3-yl-
lithium (2e).
ylsulfanyl-2-(prop-1-ynyl)ben-
zene, the product derived from
the ring opening, was obtained
in 78% yield at tR1 =3.1 s and
T=248C.
By using the optimized condi-
tions for the generation of 2d
[tR1 =0.014 (T=24), 0.055 (0), 1.6
(À28), tR1 =1.6 s (À488C)], the
subsequent reaction with octa-
Scheme 8. Br/Li exchange reaction of 1e with nBuLi and subsequent twofold addition–elimination reaction with
octafluorocyclopentene.
fluorocyclopentene was investigated by using the integrated
flow microreactor system shown in Figure 1b. As shown in
Figure 9, the reaction could be conducted at 08C, but the yield
Br/Li exchange of 1e was slower than that of 1d (Figure 8a),
although quantitative conversions were obtained in the high
temperature–long residence time region. The high yield region
for 2-methylbenzofuran in Figure 10b is slightly smaller than
of
1,2-bis(2-methyl-1-benzothiophen-3-yl)perfluorocyclopen-
Figure 9. Temperature–residence time (in R2) map for the Br/Li exchange re-
action of 1d with nBuLi followed by the reaction with octafluorocyclopen-
tene in an integrated flow microreactor system. Contour plot with scatter
overlay of the yield of 4dd indicated by numbered circles.
Figure 10. Temperature–residence time (in R1) map for the Br/Li exchange
reaction of 1e with nBuLi followed by the reaction with methanol. a) Con-
tour plot with scatter overlay of the conversion of 1e, b) contour plot with
scatter overlay of the yield of 2-methylbenzofuran and c) contour plot with
scatter overlay of the yield of 1-hydroxy-2-(prop-1-ynyl)benzene; conversion
and yields indicated by numbered circles.
tene (4dd) was very low presumably because 2d remained un-
changed. However, at a longer residence time (tR2 =57 s), 4dd
was obtained in reasonable yield (56% at À288C).
Br/Li exchange reaction of 1e followed by reaction with octa-
fluorocyclopentene
that for 2,3-dimethylbenzothiophene (Figure 8b), implying that
2e is slightly less stable than 2d. In the high temperature–
long residence time region, 1-hydroxy-2-(prop-1-ynyl)benzene,
the product derived from the ring-opening of 2e, was ob-
tained in good yields. Figure 11 clearly demonstrates the differ-
Diarylethenes with benzofuran units undergo a fatigue-resist-
ant photochromic reaction, even in the single-crystalline
phase.[4f,21] Therefore, a symmetrical diarylethene with benzo-
furan units was synthesized by the Br/Li exchange reaction of
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Synthesis of Photochromic Diarylethenes
aged that the development of an effective method for the
synthesis of unsymmetrical diarylethenes would open a new
possibility for photochromism.
Recent investigations revealed that the selectivity of fast,
competitive, consecutive reactions could be significantly im-
proved by using flow microreactor systems.[8c,9h,22] If a reaction
is faster than mixing, the reaction occurs before the homoge-
neity of the solution is achieved. This often happens in batch
macroreactors, such as flasks. In such cases, arguments based
on kinetics do not work, and product selectivity is determined
by the manner of mixing (disguised chemical selectivity).[23] To
obtain a predictable selectivity close to a kinetically based one,
extremely fast mixing is necessary, and micromixing based on
short diffusion paths is effective for this purpose. Selective
monoarylation by extremely fast 1:1 micromixing of an aryl-
lithium and octafluorocyclopentene would lead to an effective
method for the synthesis of unsymmetrical diarylethenes
through sequential arylation of octafluorocyclopentene with
two different aryllithiums (Scheme 9).
Figure 11. Plots of the yields of the products obtained without ring opening
of the heteroaryllithium intermediates against the residence time (tR1) at
À288C in the flow microreactor system. a) 2,3-Dimethylbenzothiophene and
b) 2-methylbenzofuran.
ence in the reactivity between 2d and 2e: the former is pro-
duced within 0.01 s, whereas the latter is produced more
slowly because Br/Li exchange is slower, but the latter isomer-
izes more rapidly through ring opening, although the reason
for this difference in reactivity is not clear at present. Precise
control of the residence time and temperature enables switch-
ing of the pathways. It is also important to note that the resi-
dence time–temperature maps serve as powerful tools for ana-
lyzing the behavior of reactive intermediates.
By using the optimized conditions for the generation of 2e
[tR1 =0.014 (T=24), 0.055 (0), 0.22 (À28), 3.1 s (À488C)], the
subsequent reaction with octafluorocyclopentene was investi-
gated by using the integrated flow microreactor system shown
in Figure 1b. As shown in Figure 12, the reaction could be con-
ducted at 08C, but the yield of 1,2-bis(2-methyl-1-benzofuran-
3-yl)perfluorocyclopentene (4ee) was very low presumably be-
cause 2e remained unchanged. However, at a longer residence
time (tR2 =57 s, beyond the region shown in Figure 12), 4ee
was obtained in reasonable yield (51% at À288C).
Scheme 9. Synthesis of photochromic unsymmetrical diarylethene. a) Selec-
tive monoarylation of octafluorocyclopentene and b) reaction of the mono-
arylated compound with other heteroaryllithium compounds.
Monoarylation of octafluorocyclopentene with heteroaryl-
lithium
We examined the monoarylation of octafluorocyclopentene
using one equivalent of an aryllithium. (2-Methyl-5-phenyl-3-
thienyl)lithium (2a, Ar1Li generated from 1a) or (5-methyl-2-
phenyl-4-thiazolyl)lithium (2c, Ar1Li generated from 1c) was
used as an aryllithium. Before using the flow microreactor
system, we examined the reactions in a conventional flask.
A solution of nBuLi (0.42m in hexane, 1.5 mL) was added
dropwise to a solution of 1a or 1c (0.10m in THF, 6 mL) at
temperature T. After stirring for 10 min at the same tempera-
ture, a solution of octafluorocyclopentene (0.15m in THF, 4 mL)
was added. After stirring for 10 min, the yields of the monoary-
lated products, 1-(2-methyl-5-phenyl-3-thienyl)perfluorocyclo-
pentene (3a) or 1-(5-methyl-2-phenyl-4-thiazolyl)perfluorocy-
clopentene (3c), and the yields of the diarylated products, 4aa
or 4cc, were determined by using GC. As shown in Table 1, the
yield and selectivity of monoarylated product were not high in
all cases.
Figure 12. Temperature–residence time (in R2) map for the Br/Li exchange
reaction of 1e with nBuLi followed by the reaction with octafluorocyclopen-
tene in an integrated flow microreactor system. Contour plot with scatter
overlay of the yield of 4ee indicated by numbered circles.
Synthesis of unsymmetrical diarylethenes
Many photochromic diarylethenes reported in the literature
are symmetrical presumably because asymmetrically substitut-
ed diarylethenes are difficult to synthesize. Therefore, we envis-
ChemSusChem 2012, 5, 339 – 350
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345

J.-i. Yoshida et al.
3.0 mLminÀ1) in M3 (f=500 mm) to quench any unchanged
aryllithium very quickly. The resulting solution was passed
through R3 (tR3 =1.6 s). The results obtained by varying tR1 and
T are shown in Table 2. The monoarylated product could be
obtained with high selectivity at 0 and 248C in the flow micro-
reactor system by using one equivalent of the aryllithium. Ex-
tremely fast mixing in the flow microreactor system seems to
be responsible for these results.
Table 1. The Br/Li exchange reaction of 1a or 1c (1 equiv) with nBuLi
(1.05 equiv) followed by the reaction with octafluorocyclopentene in a
conventional batch macroreactor.[a]
Ar1Br
T
[8C]
Products [%]
diarylated
Table 2. The Br/Li exchange reaction of 1a or 1c (1 equiv) with nBuLi
(1.05 equiv) followed by the reaction with octafluorocyclopentene in an
integrated flow microreactor system.[a]
monoarylated
Ar1Br
T
tR2
[8C] [s]
Products [%]
diarylated
monoarylated
À78
24
18
24 8.2 66
6
11
9
0
0.51 77
2.0 81
8.2 77
À78
17
19
9
2
11
0
[a] A solution of nBuLi (0.42m in hexane, 1.5 mL) was added dropwise to
a solution of 1a or 1c (0.10m in THF, 6 mL) at temperature T. After stir-
ring for 10 min at the same temperature, a solution of octafluorocyclo-
pentene (0.15m in THF, 4 mL) was added. After stirring for 10 min, the
yields of 3a, 4aa, 3c, and 4cc were determined by using GC.
24 8.2 74
6
0
0
3
0
0.51 25
2.0 46
8.2 65
In the next step, the reaction was examined by using an
integrated flow microreactor system composed of three
T-shaped micromixers (M1, M2, and M3) and three microtube
reactors (R1, R2, and R3), as shown in Figure 13. A solution of
1a or 1c (0.10m in THF; flow rate: 6.0 mLminÀ1) and a solution
of nBuLi (0.42m in hexane; flow rate: 1.5 mLminÀ1) were intro-
duced into M1 (f=500 mm) by using syringe pumps. The re-
sulting solution was passed through R1 [1a: tR1 =0.22 (T=24),
0.38 s (08C); 1c: tR1 =0.79 s (T=24 and 08C)] and then mixed
with a solution of octafluorocyclopentene (0.15m in THF; flow
rate: 4.0 mLminÀ1) in M2 (f=500 mm). The resulting solution
was passed through R2 and mixed with methanol (flow rate:
[a] The yields of 3a, 4aa, 3c, and 4cc were determined by using GC.
Synthesis of unsymmetrical diarylethenes by the reaction of a
monoarylated compound and an aryllithium
Based on the successful monoarylation using the flow micro-
reactor system, we examined the introduction of a second aryl
group (Ar2) to a monoarylated compound by using an integrat-
ed flow microreactor system composed of three T-shaped mi-
cromixers (M1, M2, and M3) and three microtube re-
actors (R1, R2, and R3), as shown in Figure 14. A solu-
tion of 1b, 1c, 1d, or 1e (0.10m in THF; flow rate:
4.8 mLminÀ1) and a solution of nBuLi (0.42m in
hexane; flow rate: 1.2 mLminÀ1) were introduced to
M1 (f=500 mm) by using syringe pumps. The result-
ing solution was passed through R1 [1b: tR1 =0.98 s
(T=08C), 1c: tR1 =0.47 s (T=248C), 1d: tR1 =2.0 s
(T=À288C), 1e: tR1 =0.28 s (T=À288C)] and then
mixed with a solution of 3a or 3c (0.052m in THF;
flow rate: 9.2 mLminÀ1) in M2 (f=500 mm). The re-
Figure 13. An integrated flow microreactor system for the Br/Li exchange reaction of 1a
or 1c (1 equiv) with nBuLi (1.05 equiv) followed by the reaction with octafluorocyclopen-
tene (micromixers: M1, M2, and M3; microtube reactors: R1, R2, and R3).
sulting solution was passed through R2 [1b: tR2 =
5.2 s (T=248C), 1c: tR2 =5.2 s (T=248C), 1d: tR2 =
346
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ChemSusChem 2012, 5, 339 – 350

Synthesis of Photochromic Diarylethenes
Table 3. The reactions of monoarylated compounds (3a and 3c) with
heteroaryllithium compounds generated from 1b, 1c, 1d, and 1e in an
integrated flow microreactor system.[a]
Ar2Br
Unsymmetrical
diarylated product [%]
Figure 14. An integrated flow microreactor system for the Br/Li exchange re-
action of 1b, 1c, 1d, or 1e with nBuLi followed by reaction with 3a or 3c
(micromixers: M1, M2, and M3; microtube reactors: R1, R2, and R3).
68
94
35
68
79
55
82
30 s (T=À288C), 1e: tR2 =30 s (T=À288C)] and mixed with
methanol (flow rate: 3.0 mLminÀ1) in M3 (f=500 mm) to
quench unreacted lithium species very quickly. The resulting
solution was passed through R3 (tR3 =1.3 s). As shown in
Table 3, the introduction of two different aryl groups to octa-
fluorocyclopentene was successfully achieved.
Synthesis of unsymmetrical diarylethenes from octafluoro-
cyclopentene by sequential introduction of two aryl groups
Finally, the sequential introduction of two different aryl groups
to octafluorocyclopentene was examined by using an integrat-
ed flow microreactor system composed of four T-shaped mi-
cromixers (M1, M2, M3, and M4) and four microtube reactors
(R1, R2, R3, and R4), as shown in Figure 15. A solution of 1a or
1c (0.10m in THF; flow rate: 4.8 mLminÀ1) and a solution of
nBuLi (0.42m in hexane; flow rate: 1.2 mLminÀ1) were intro-
duced into M1 (f=500 mm) by using syringe pumps. The re-
sulting solution was passed through R1 [1a: tR1 =0.28 s (T1 =
08C), 1c: tR1 =0.98 s (T1 =248C)] and mixed with a solution of
octafluorocyclopentene (0.15m in hexane; flow rate:
3.2 mLminÀ1) in M2 (f=500 mm). The mixture was then
passed through R2 [tR2 =2.6 s (T1 =0 and 248C)]. A solution of
1b or 1c (0.10m in THF; flow rate: 4.8 mLminÀ1) and a solution
of nBuLi (0.42m in hexane; flow rate: 1.2 mLminÀ1) were intro-
duced into M3 (f=500 mm), and the resulting solution was
passed through R3 [1b: tR3 =2.0 s (T2 =08C), 1c: tR3 =0.98 s
(T2 =248C)] and introduced to M4 (f=500 mm), where the so-
lution was mixed with the solution from R2. The resulting solu-
tion was passed through R4 [1b: tR4 =5.7 s (T2 =08C), 1c: tR4 =
6.2 s, T2 =248C)]. Selective synthesis of unsymmetrical diaryle-
thenes was easily accomplished using two different aryl bro-
mides, as shown in Table 4. The results indicate the possibility
of fine-tuning of the physical properties by introducing differ-
ent heteroaromatic substituents into the alkene framework by
taking advantage of the microreactor system.
[a] The yields were determined by using GC.
Conclusions
We have developed an effective method for the synthesis of
photochromic diarylethenes by using integrated flow micro-
ChemSusChem 2012, 5, 339 – 350
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www.chemsuschem.org
347

J.-i. Yoshida et al.
Experimental Section
Typical procedure for the halogen–lithium exchange reaction of
heteroaryl halides followed by reaction with an electrophile in flow
microreactor systems: A flow microreactor system that consisted of
two T-shaped micromixers [M1 (f=500 mm) and M2 (f=500 mm)],
two microtube reactors [R1 and R2 (inner diameter f=1000 mm,
length L=200 cm)], and three tube precooling units [P1 (f=
1000 mm, L=100 cm), P2 (f=1000 mm, L=50 cm), and P3 (f=
1000 mm, L=100 cm)] was used. A solution of a heteroaryl halide
(0.100m in THF; flow rate: 6.00 mLminÀ1) and a solution of nBuLi
(0.420m in n-hexane; flow rate: 1.50 mLminÀ1) were introduced
into M1 by using syringe pumps. The resulting solution was
passed through R1 and mixed with a solution of iodomethane
(0.600m in THF) or methanol (neat; flow rate: 3.00 mLminÀ1) in
M2. The resulting solution was passed through R2. After a steady
state was reached, the product solution was collected for 30 s
while being quenched with H2O. Brine (5 mL) was added, and the
organic layer was analyzed by using GC.
Figure 15. An integrated flow microreactor system for the sequential intro-
duction of two different heteroaryl groups onto perfluorocyclopentene (mi-
cromixers: M1, M2, M3, and M4; microtube reactors: R1, R2, R3, and R4).
Table 4. Synthesis of unsymmetrical diarylethenes from octafluorocyclo-
pentene by the sequential introduction of two heteroaryl groups in inte-
grated flow microreactor systems.[a]
Typical procedure for the halogen–lithium exchange reaction of
heteroaryl halides (2 equiv) and reaction with octafluorocyclopen-
tene in integrated flow microreactor systems: An integrated flow
microreactor system that consisted of three T-shaped micromixers
[M1 (f=500 mm), M2 (f=500 mm), and M3 (f=500 mm)], three
microtube reactors [R1, R2, and R3 (f=1000 mm, L=50 cm)], and
four tube precooling units [P1 (f=1000 mm, L=100 cm), P2
(f=1000 mm, L=50 cm), P3 (f=1000 mm, L=100 cm), and P4 (f=
1000 mm, L=100 cm)] was used. A solution of a heteroaryl halide
(0.100m in THF; flow rate: 6.00 mLminÀ1) and a solution of nBuLi
(0.420m in n-hexane; flow rate: 1.50 mLminÀ1) were introduced
into M1 by using syringe pumps. The resulting solution was
passed through R1 and mixed with a solution of an octafluorocy-
clopentene (0.130m in THF; flow rate: 2.00 mLminÀ1) in M2. The
resulting solution was passed through R2. The resulting solution
was mixed with methanol (neat; flow rate: 3.00 mLminÀ1) in M3 to
quench unreacted lithium species very quickly. The resulting solu-
tion was passed through R3. The generation of heteroaryllithiums
and the following reaction with an octafluorocyclopentene were
conducted at the same temperature. After a steady state was
reached, the product solution was collected for 30 s while being
quenched with H2O. Brine (5 mL) was added, and the organic layer
was analyzed by using GC.
Ar1Br
Ar2Br
Unsymmetrical
diarylated product [%]
58
51
66
Typical procedure for the sequential introduction of two different
heteroaryl groups into perfluorocyclopentene in an integrated flow
microreactor system: An integrated flow microreactor system that
consisted of four T-shaped micromixers [M1 (f=500 mm), M2
(f=500 mm), M3 (f=500 mm), and M4 (f=500 mm)], four micro-
tube reactors [R1 (f=1000 mm), R2 (f=1000 mm), R3 (f=
1000 mm), and R4 (f=1000 mm)], and five tube precooling units
[P1 (f=1000 mm, L=100 cm), P2 (f=1000 mm, L=50 cm), P3
(f=1000 mm, L=100 cm), P4 (f=1000 mm, L=100 cm), and P5
(f=1000 mm, L=50 cm)] was used. A solution of a heteroaryl
halide (Ar1Br; 0.10m in THF; flow rate: 4.8 mLminÀ1) and a solution
of nBuLi (0.42m in hexane; flow rate: 1.2 mLminÀ1) were intro-
duced into M1 by using syringe pumps. The resulting solution was
passed through R1 and mixed with a solution of an octafluorocy-
clopentene (0.15m in hexane; flow rate: 3.2 mLminÀ1) in M2. The
mixture was passed through R2. A solution of a heteroaryl halide
(Ar2Br; 0.10m in THF; flow rate: 4.8 mLminÀ1) and a solution of
nBuLi (0.42m in hexane; flow rate: 1.2 mLminÀ1) were introduced
into M3, and the resulting solution was passed through R3 and in-
troduced to M4, where the solution was mixed with the solution
from R2. The resulting solution was passed through R4. After a
[a] The yields were determined by using GC.
reactor systems. The practical synthesis of symmetrical and un-
symmetrical diarylethenes with thiophene, thiazole, benzothio-
phene, and benzofuran rings was achieved without using cryo-
genic conditions by fully optimizing the temperatures and the
residence times in a halogen–lithium exchange reaction and
subsequent reaction with octafluorocyclopentene. The success-
ful synthesis of unsymmetrical diarylethenes using two differ-
ent aryl bromides indicates the potential for using the flow mi-
croreactor system to make new functional materials that are
otherwise difficult to synthesize in a conventional way. Because
several micro chemical plants on pilot scales have already
been built, it is hoped that this process will be transformed for
industrial production with continuous operation.
348
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ChemSusChem 2012, 5, 339 – 350

Synthesis of Photochromic Diarylethenes
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steady state was reached, the product solution was collected for
30 s while being quenched with H2O. Brine (5 mL) was added, and
the organic layer was analyzed by using GC. The results are sum-
marized in Table S14 in the Supporting Information.
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Acknowledgements
This work was partially supported by NEDOs.
Keywords: diarylethenes
· microreactors · organometallic
compounds · photochromism
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Published online on November 8, 2011
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