Chemical Engineering Journal 167 (2011) 567–571

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Chemical Engineering Journal
journal homepage: www.elsevier.com/locate/cej

Microﬂow photo-radical chlorination of cycloalkanes
Hiroshi Matsubara ∗∗ , Yoshiko Hino, Masashi Tokizane, Ilhyong Ryu ∗Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japana r t i c l ei n f o

Article history:
Received 8 May 2010
Received in revised form 11 August 2010
Accepted 16 August 2010
Keywords:
Microreactor
Radical chlorination
Sulfuryl chloride
Molecular chlorinePhotoreactiona b s t r a c t
Photo-initiated radical chlorination of cycloalkanes was investigated using microﬂow reactors. Under
natural light, microﬂow chlorination of cyclohexane with molecular chlorine proceeded well to givechlorocyclohexane with high selectivity for single-chlorination. Single-chlorination reaction of cycloalkanes with sulfuryl chloride can also be successfully carried out using a microﬂow reactor under irradiation
using a 15 W black light.
© 2010 Elsevier B.V. All rights reserved.

1. Introduction
The recent rapid progress of microﬂow reaction technology led
synthetic organic chemists to examine a variety of organic reactions
using microreactors [1,2]. Since microﬂow reactors provide highheat and mass transfer rate for organic reactions, those reactions
which are difﬁcult to control using conventional batch equipments
can be a potential target for the improvement. Work in our laboratories has been directed toward the design and application of
microﬂow reaction technologies to conventional organic synthesis[3] and to the end, we previously reported on effective continuous
microﬂow reactions, which include Pd-catalyzed coupling reactions in ionic liquids [4], thermally induced radical reactions [5] andphoto-irradiation reactions [6]. Photoreactions using microreactors
have promise to use light energy at minimum because the lightpenetration is ideal inherent to the thinness of the microreactor
and the resultant short residence time even allows the avoidanceof undesirable second reactions [7,8]. As such an application ofphoto-irradiation reactions, we recently reported on a successful multi-gram-scale production of a steroidal compound by theBarton reaction using a microﬂow reactor in combination with anenergy saving light source such as black light [9]. We also achieved
diastereoselective [2+2] photoaddition reactions using a microﬂow
system [10].
As part of our ongoing interest in organic synthesis by
microﬂow photo-irradiation technologies, we began to investigate
radical chlorination of alkanes using a microreactor under photo-∗ Corresponding author. Tel.: +81 72 254 9695; fax: +81 72 254 9695.
∗∗ Co-corresponding author.
E-mail address: ryu@c.s.osakafu-u.ac.jp (I. Ryu).
1385-8947/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.cej.2010.08.086

irradiation conditions. Radical chlorination of alkanes is one of themost basic organic reactions, and studies on this reaction continue for more than half century [11–13]. While various reagentsincluding molecular chlorine [11] and sulfuryl chloride [12] areused for radical chlorination of alkanes with variable selectivity[14], in order to achieve reproducible selectivity for single chlorination over competing polychlorination, strict control of molar ratios,
light power, and reaction time are required for batch systems. Wethought that radical chlorination in a microﬂow system would beuseful even for alkane chlorination in terms of controlled selectivity, efﬁciency with energy saving light sources. Although radicalchlorination using a microﬂow system was previously reported forchlorination of a benzylic position [15–17], no work on chlorination of simple alkanes using a microreactor has been reported; wereport herein radical chlorination of cyclic alkanes using sulfuryl
chloride and molecular chlorine can be effectively carried out using
a continuous microﬂow system and visible lights.

2. Experimental
2.1. General information
GC analysis was performed with a SHIMADZU GC-18A; column:
J&W DB-1 (i.d.: 0.32 mm, length: 30 m, ﬁlm: 1 ␮m), N2 (700 kPa);
temperature program: 60 ◦ C for 6 min, then 60–250 ◦ C at 20 ◦ C/min.
GC yields were determined by comparing the peak area with that of
the standard solution containing an authentic sample. All productsin this study are known and commercially available; their spectral
data are in agreement with the authentic samples.
Microﬂow chlorinations were carried out using a DNS F005D03HB (1000 ␮m width, 300 ␮m depth and 2.35 m length, and total

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H. Matsubara et al. / Chemical Engineering Journal 167 (2011) 567–571

Fig. 1. DNS microreactor F005D03-HB.

hold-up volume: 0.7 mL, by Dainippon Screen Mfg. Co., Ltd., Japan)
under natural light or a Mikroglas Dwel Device (1000 ␮m width,500 ␮m depth and 1.9 m length, and total hold-up volume: 0.95 mL,by Mikroglas Chemtech GmbH, Germany) attached with a 15 W
black lights. Inline check valve (6.9 MPa, CV-3000, GL-Sciences Inc.,Japan) was used for the chlorination reaction with molecular chlorine.
2.2. Procedure for a continuous microﬂow chlorination ofcyclohexane with molecular chlorine
The continuous microﬂow system was comprised of a T-shaped
micromixer (i.d. = 500 ␮m) and the DNS reactor, two gas/liquid feed
stainless tube and an outlet. A 10 mL gas tight syringe containing cyclohexane (5 mL, 46 mmol) was attached to an inlet of themicromixer and a 25 mL gas tight syringe containing molecularchlorine (25 mL, 1.1 mmol) was connected to the other inlet ofthe micromixer through a check valve. The syringes were pumped
using syringe pumps at ﬂow rates of 1.32 mL/h and 7.68 mL/h
for cyclohexane and molecular chlorine, respectively (residencetime: 19 min). The mixture of product eluted from the outlet wascollected in a ﬂask containing 10% sodium sulﬁte. Yield of chlorocyclohexane was determined by GC analysis.
2.3. General procedure for a continuous microﬂow chlorination ofcycloalkane with sulfuryl chloride
A 10 mL gas tight syringe containing a mixture of sulfuryl chloride (283 mg, 2.1 mmol) in cyclohexane (6.73 g, 80.0 mmol) was
attached to the inlet of the Mikroglas device. The syringe wasFig. 2. Microﬂow chlorination with molecular chlorine.

H. Matsubara et al. / Chemical Engineering Journal 167 (2011) 567–571

569

Fig. 3. Devices for microﬂow chlorination using sulfuryl chloride.

pumped using syringe pumps at ﬂow rates of 1 mL/h or 3 mL/h(residence time: 57 min or 19 min) under photo irradiation using a15 W of black light. The microreactor was cooled with water during the reaction. A mixture eluted from the outlet was collected ina ﬂask containing 10% sodium sulﬁte. Yield of chlorocyclohexane
was determined by GC analysis.
3. Results and discussion
3.1. Microﬂow chlorination of cyclohexane with molecularchlorine and room light
We started our chlorination study using a microﬂow systemwith cyclohexane as the substrate. We chose a DNS microreactor F005D03-HB composed of photo-etched stain-less steel
microchannels with covered Pyrex glass (Fig. 1, 1000 ␮m width,
300 ␮m depth and 2.35 m length, and total hold-up volume: 0.7 mL)

for this reaction. The total ﬁgure of the ﬂow reaction system isshown in Fig. 2. Thus, the DNS microreactor was connected witha T-shaped micromixer (i.d. = 500 ␮m), and a check valve (6.9 MPa)
was ﬁtted to one of the inlets of the micromixer for avoiding backward ﬂow of chlorine. As molecular chlorine is known to react withalkanes violently under UV irradiation, we used natural room lightas the light source. Thus, we carried out chlorination of cyclohexanewith molecular chlorine at room temperature in natural light withresidence time of 19 min (measured value). As we envisioned thereaction gave chlorocyclohexane with nearly complete selectivity
for single chlorination product (>95%) in the yield of 20%.
3.2. Microﬂow chlorination with sulfuryl chloride and black light
We then examined chlorination using sulfuryl chloride as a chlorination reagent. As sulfuryl chloride is known to react more gently
than molecular chlorine, a 15 W black light (peak wavelength:

Fig. 4. Microﬂow chlorination with sulfuryl chloride.

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H. Matsubara et al. / Chemical Engineering Journal 167 (2011) 567–571

Table 1
Microﬂow chlorination of cycloalkanes with sulfuryl chloride.a+Mikroglas, r.t.

nn40 equiv.
EntryClhν (black light, 15W)
SO2Cl2n = 0, 1, 2, 3 .
Substrate

Flow rate(mL/h)

Residencetime (min)Yield ofchlorocycloalkane (%)b1

3.0

19

222c

3.0

19

20

3

1.0

57

35

4d

1.0

57

375e

1.057

45

6

3.0

1941

7

1.057

61

8

1.0

57

87

9

1.057

47

Fig. 5. Without BPR (plug ﬂow).

Fig. 6. With BPR (plug ﬂow suppressed).

aReaction conditions: Mikroglas Dwel Device, cycloalkane (80 mmol), sulfuryl
chloride (2.1 mmol), and 15 W black light, r.t.
bGC yield.
cCyclohexane 80 equiv.
dUsing a back pressure regulator.
e
Using a back pressure regulator and two black lights.

352 nm) was employed for this reaction, in which a Mikroglas Dwel
Device (Foturan glass, 1000 ␮m width, 500 ␮m depth and 1.9 m
length, and total hold-up volume: 0.95 mL) was used as a microreactor. The total system for this reaction is shown in Figs. 3 and 4
and the results are summarized in Table 1. When a solution containing sulfuryl chloride and 40 molar equivalents of cyclohexane wasintroduced to a microreactor with a residence time 19 min (measured value, ﬂow rate: 3.0 mL/h) at room temperature, the reaction
gave chlorocyclohexane selectively in 22% yield (entry 1). While
increasing molar ratio of cyclohexane to 80 equiv. did not affectthe yield of the product (20%, entry 2), extending residence time
(57 min, ﬂow rate: 1.0 mL/h) raised product yield to 35% (entry 3).
As shown in Fig. 5, plug ﬂow was observed due to gases of SO2 andHCl generated during the reaction. To avoid occasional disturbanceby the plug ﬂow in the microreactor, a back pressure regulator (BPR:Upchurch Scientiﬁc, P-790, 0.3 bar) was ﬁtted, resulting in the effective suppression of the plug ﬂow (Fig. 6). The reaction using two
black lights resulted in slightly better yield of the product (entry5).
Microﬂow chlorinations of cyclopentane, cycloheptane andcyclooctane were also carried out (entries 6–9). Again, decreasein the yield was observed using faster ﬂow rate for the case ofcyclopentane (entry 6). Under the employed conditions all chlo-rination reactions proceeded well to give monochlorocycloalkanes
with high selectivity (>95%) [18].
4. Conclusions
In summary, we have demonstrated that radical chlorination
reaction of cycloalkanes with molecular chlorine and sulfuryl
chloride using a microﬂow reactor proceeded well under photoirradiation conditions (natural light and black light) to givechlorocycloalkanes with high selectivity for single chlorination. In
the reaction using sulfuryl chloride, plug ﬂow inherent to the gas
evolution was effectively suppressed by the use of a back-pressure
regulator.
Acknowledgements
We thank MCPT and NEDO for generous support of this work.
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