DOI: 10.1002/chem.201402303

Communication& Selective Bromination

Revisiting the Bromination of C H Bonds with Molecular Bromine
by Using a Photo-Microflow System
Yoshiyuki Manabe,[a] Yuriko Kitawaki,[a] Masahiro Nagasaki,[a] Koichi Fukase,*[a]Hiroshi Matsubara,[b] Yoshiko Hino,[b] Takahide Fukuyama,[b] and Ilhyong Ryu*[b]Abstract: The photobromination of C H bonds by using
molecular bromine was reinvestigated under microfluidic
conditions. The continuous-flow method suppressed the
production of dibrominated compounds and effectively
produced the desired monobrominated products withhigh selectivity. Rapid bromination of benzylic substrates
containing a photoaffinity azide group was achieved without any decomposition.

Organobromine compounds are among the most versatile intermediates in organic synthesis. They serve as precursors tocarbanions, carbon radicals, carbocations, and organo–transition-metal species.[1] Among the various methodologies to prepare bromoalkanes, the most straightforward is the direct conversion of C H bonds into C Br bonds by using molecular bromine; this method originated a century ago.[2] Kharasch andcoworkers established the reactivity of this method towards
different C H bonds and radical-chain mechanisms.[3] A bromine radical, arising from homolysis of molecular bromine byphotoirradiation, abstracts a hydrogen atom from a C H bondto form a carbon radical, liberating HBr. The resulting carbon
radical then abstracts a bromine atom from molecular bromine
to give a C Br bond, liberating a bromine radical, which participates in the next radical chain.
The disadvantage of this synthetic procedure is that the sideproducts include a significant amount of 1,2-dibromoalkanes.
A recent study using a batch flask reported that photobromination of cyclohexane (1 a) with a stoichiometric amount ofmolecular bromine in water gives a 3:2 mixture of desired bromocyclohexane (2 a) and undesired trans-1,2-dibromocyclohexane (3 a).[4,5][a] Dr. Y. Manabe, Y. Kitawaki, M. Nagasaki, Prof. K. Fukase
Department of chemistry, Graduate School of Science
Osaka University
Toyonaka, Osaka 560-0043 (Japan)
Fax: (+ 81) 6-6850-5391
E-mail: koichi@chem.sci.osaka-u.ac.jp[b] Prof. H. Matsubara, Y. Hino, Prof. T. Fukuyama, Prof. I. Ryu
Department of Chemistry, Graduate School of Science
Osaka Prefecture University
Sakai, Osaka 599-8531 (Japan)
E-mail: ryu@c.s.osakafu-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402303.
Chem. Eur. J. 2014, 20, 12750 – 12753

Recently, photoreactions have been investigated by using
microreactors,[6,7] which enable efficient photoirradiation andrealize a reproducible and energy-saving system. In general,
microreactors suppress undesired over-reactions because theflow-reaction system allows the products to be rapidly transferred from the reactor. Consequently, various microfluidic processes for photoreactions, such as photoadditions, photorearrangements, photooxygenation, and specific examples of photohalogenation, have been examined.[8] This study aims tomodernize the photoinduced C H/C Br conversion by molecular bromine by using microfluidic processes. Recent researchhas demonstrated that effective a-bromination of alkylbenzenes is possible based on microflow photobromination using
bromine-related reagents, such as HBr H2O2 and N-bromosuccinimide (NBS).[9]We examined the flow bromination of cyclohexane with molecular bromine under visible-light irradiation (15 W black light,
peak wavelength 352 nm) by using microflow devices(Scheme 1, Table 1). When a cyclohexane solution of Br2 (Br2/

Scheme 1. Microflow devices for photobromination of cyclohexane (1 a).

1 a = 1:5) was mixed with water by using a micromixer (diameter 500 mm), and the mixture subsequently introduced intoa glass-made flow device with a residence photoirradiation
time of 19 min, bromocyclohexane (2 a) was formed in 42 %yield, together with a 13 % yield of 1,2-dibromocyclohexane(3 a) (entry 1). A higher selectivity of 2 a/3 a was attained whena larger excess of cyclohexane was used (entries 2–4). For example, an 80-fold excess of 1 a increased the selectivity of 2 a/
3 a to 96:4 (entry 5). The residence time could be reduced to
5.7 min (entry 7), whereas the reaction using a batch reactor(Pyrex, 3 cm internal diameter test tube) gave only 11 % conversion. The use of two black-light bulbs (30 W) further increased the reaction rate with a residence time of 2.9 min(entry 8).
After successfully converting C H bonds into C Br bonds,
microflow photobromination was then applied to various alkanes (Table 2). Continuous-flow bromination of cyclopentane

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Communicationceeded even under ambient light. Thus, a FC-72 (perfluorohexanes) solution of bromine with these alkanes was mixed byusing an additional micromixer, and the resulting mixture wasquickly mixed with water. These reactions occurred selectively
at the tertiary C H bond, giving corresponding tertiary alkyl
bromides 2 e, 2 f, and 2 g in good yields (entries 5–7).
The ability of Br2 to convert C H bonds into C Br bonds ismuch less than that of Cl2 or F2 for C H/C Cl or C H/C F conversion, respectively.[10] However, Br2 provides site selectivity.
The site selectivity of the photoinduced C H/C Br conversion
is tertiary alkyl > secondary alkyl > primary alkyl. This trend canbe rationalized by the low-barrier transition states for H-atom
abstraction by the bromine radical, predicted by DFT calculations (Scheme 2).[11] It is interesting to compare H-atom ab-

Table 1. Photoinduced continuous-flow bromination of cyclohexane (1 a).

Entry[a]Residencetime [min]Ratio of
1 a/Br2

Yield [%][b]2a3aSelectivity
for 2 a [%]

1
2
3
4
5
6
7
8[c]

19
19
19
19
19
9.5
5.7
2.9

5:1
10:1
40:1
60:1
80:1
40:1
40:1
40:1

42
78
84
87
96
80
78
77

76
86
91
95
96
89
90
92

13
13
8
5
4
10
9
7

[a] Reaction conditions: Br2 (0.5 mmol), Mikroglas Dwel Device (channel
size: 500 mm deep, 1000 mm wide, and 1.9 m long, Foturan glass), Micromixer (500 mm) and 15 W black light (352 nm), room temperature. [b] Determined by GC analysis with chlorobenzene as an internal standard.
[c] Two bulbs of black light (total 30 W) were used.

Table 2. Photoinduced flow bromination of various alkanes.
Entry[a]Substrate

Product

Yield [%][b]Selectivity
for 2 [%]

1

1a

2a

84

91

2

92

93

3

99

99

4

93

94

5[c]

58

84

6[c,d]

76

87

7[c,e]

58

Scheme 2. Transition states for H-atom abstraction from C H bonds by thebromine radical (energies (in kJ mol 1) calculated at the BHandHLYP/6311 + + G(d,p) + LanL2DZdp(Br) level).

99[a] Reaction conditions: Br2 (0.5 mmol), 1 (40 equiv), Mikroglas Dwel
Device (channel size: 500 mm deep, 1000 mm wide, 1.9 m long) Micromixer (500 mm) and 15 W black light (Toshiba, 352 nm), room temperature,
residence time = 19 min. [b] Determined by GC analysis. [c] Alkanes weremixed with a FC-72 (perfluorohexanes) solution of molecular bromine byusing a micromixer. The resulting solution was mixed with water by using
a second micromixer (for details, see the Supporting Information).
[d] Two stereoisomers of 2 f (product ratio = 4:1) were detected by GC
analysis and 1H NMR spectroscopy. [e] Residence time = 1.9 min.

(1 b), cycloheptane (1 c), and cyclooctane (1 d) gave the corresponding bromocycloalkanes (2 b, 2 c, and 2 d) in good yields
with high selectivity (entries 2, 3, and 4). Bromination of substrates with a tertiary C H bond, such as 1 e, 1 f, and 1 g, proChem. Eur. J. 2014, 20, 12750 – 12753

www.chemeurj.org

straction, by the bromine radical, of trimethylmethane and toluene. Although both have almost identical activation energies,
the energy barrier of the backward reaction with the tertiary
butyl radical is more facile than that with the benzyl radical,
predicting that benzylic bromination is more likely. Therefore,
we then focused on flow photobromination of alkylarenes byusing Br2.
a-Brominated alkylbenzenes have diverse applications in organic synthesis, especially as benzylation reagents. Consequently, numerous methods have been developed for bromination of the benzylic position, including using molecular bromine,[12] NBS,[13] H2O2/HBr,[14] or NaBrO3/NaHSO3.[15] Herein, we
focused on flow photobromination using molecular bromine,
which is a simple and cost-effective bromine source. Using 4phenyltoluene (4 a) as a model substrate, we examined flow
photobromination (Table 3). A mixture of 4 a and 1.2 equivalents of Br2 in CCl4 was introduced into the microreactor

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Communication
give corresponding benzylic bromide 5 b in good yield(entry 2). In contrast, methyl p-methyl benzoate (4 c) requireda prolonged residence time (7.5 min) to give corresponding
monobrominated compound 5 c (entry 3). Interestingly, theflow bromination of ethylbenzene (4 d) gave monobrominatedcompound 5 d with complete selectivity (entry 4).
Next, to determine which functionalities were compatible
with the rapid flow reaction, we examined the bromination ofsubstrates with a photosensitive functionality. Thus, the benzylEntry[a]Solvent
Light
Residence
Yield
Selectivity
ic positions of p-azidotoluene (4 e) and p-benzoyltoluene (4 f),
sourcetime[%][b]
for 5 a [%]5a6awhich are sensitive to photoirradiation and widely used as
photoaffinity groups,[17] were investigated. Compound 4 e wasblack light[c]
43 s
72
11
86
1
CCl4
LED lamp[d]
43 s
75
8
90
2
CCl4
brominated, without decomposition of the parent structure, to
3.6 min
74
9
89
3
BTF
LED lamp[d]give 5 e in 80 % yield (entry 5). Although bromination of 4 f re[a] Reaction conditions: 4 a (0.1 m), Br2 (1.2 equiv), microreactor (300 mm
quired a longer residence time (2.5 min), desired product 5 f
deep, 1000 mm wide, 2.35 m long), room temperature. [b] Determined by
was obtained in 61 % yield. To the best of our knowledge, thisNMR spectroscopy. [c] 15 W black light (Toshiba, 352 nm). [d] LED lamp
is the first example of photobromination of substrates contain(YMC Co., Ltd., YMC-P-0049, 1.95 W 360 nm).
ing a photoaffinity group, such as an azide or benzoyl group,in its structure. These results demonstrate that judiciously controlled photoirradiation, coupled with a microflow reactor, ena(MiChS L-1, 300 mm deep, 1000 mm wide, 2.35 m long, quartz)
bles a highly selective benzylic bromination reaction by using
by means of a syringe pump, at a flow rate of 1.0 mL min 1,
Br2.
under black-light (15 W) irradiation (entry 1). The resultant soWe previously reported that the 4-azido-3-chloro-benzyl
lution was quenched by aqueous saturated Na2S2O3 and anagroup functions as a promising hydroxy protecting group,
lyzed by NMR spectroscopy. The reaction gave desired monowhich can be selectively cleaved by a Staudinger reduction,
brominated product 5 a in 72 %, along with 11 % of dibromifollowed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
nated byproduct 6 a. An experiment using an LED lamp
oxidation.[18] 4-Azido-3-chloro-benzylation of the hydroxy(1.95 W, peak wavelength 360 nm) gave a slightly improved
result (entry 2). CCl4 could be substituted by benzotrifluoridegroup was performed with 4-azido-3-chlorobenzyl bromide(5 g) as a benzylating reagent. Originally 5 g was synthesized(BTF)[16] as a solvent. In this case, the residence time was proby a batch bromination of 4-azido-3-chlorotoluene (4 g) bylonged from 43 s to 3.6 min (entry 3).
using NBS and 2,2’-azobis(isobutyronitrile) (AIBN) under reflux;
Table 4 lists several examples of benzylic bromination under
however, this batch reaction produced a considerable amountthe microfluidic conditions. Bromination of p-fluorotolueneof dibrominated product 6 g and a tedious chromatographic(4 b) proceeded very smoothly with a residence time of 11 s topurification was necessary to
remove the resultant succinimide. We then applied our flow
Table 4. Photoinduced flow benzylic bromination.
conditions using Br2 to obtain
Substrate
Product
Residence
Yield [%][b]Selectivity
Entry[a]5 g with high product selectivity,
time
for 5 [%]
without decomposition of thephotosensitive arylazide struc43 s
75
90
1ture. Thus, 4-azido-3-chlorotoluene (4 g) was reacted with
1.2 equivalents of molecular bro11 s
73
91
2mine under photomicrofluidic
conditions at a flow rate of
7.5 min
69
87
30.05 mL min 1, realizing a highly
selective monobromination (5 g/
8.5 s
75
100
4
6 g = 90:10,
determinedby1
H NMR spectroscopy) without
affecting the aryl azide structure
22 s
80
91
5
(Scheme 3). The resultant HBr
could be removed easily by an
2.5 min
61
87
6[c]aqueous treatment, and product5 g was easily isolated by recrys[a] Reaction conditions: 4 a–4 f (0.1 m), Br2 (1.2 equiv), microreactor (300 mm deep, 1000 mm wide, 2.35 m long),tallization from methanol in 61 %LED lamp (YMC Co., Ltd., YMC-P-0049, 1.95 W 360 nm), room temperature. [b] Determined by 1H NMR spectrosyield.
Table 3. Photoinduced flow bromination of 4 a under microfluidic conditions.

copy. [c] 1.5 equiv of Br2 was used.

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Communication

Scheme 3. Microflow photobromination of 4-azido-3-chlorotoluene (4 g).

In summary, mild and selective bromination of a variety of
C H bonds with molecular bromine is possible by using a microflow system in combination with visible-light sources. This
microfluidic method results in an excellent selectivity formonobrominated compounds, for both alkanes and benzylic
substrates, enabling the scalable and efficient preparation ofbrominated compounds, including those with photosensitive
functional groups.

Acknowledgements
This work is financially supported by a Grant-in-Aid for Scientific Research on Innovative Areas ’Reaction Integration’ (No.
2105) from the Ministry of Education, Culture, Sports, and Technology (MEXT) of Japan.
Keywords: bromination
photoreactions·

bromine·microreactors·[1] a) Halides, Pseudo-Halides and Azides in PATAI’S Chemistry of Functional
Groups Vol 1 and 2 (Eds.: S. Patai, Z. Rappoport), Wiley, Chichester,
1983; b) C. L. Hill, Activation and Functionalization of Alkanes, Wiley,
New York, 1989.
[2] For a review of earlier work on C H halogenation, see: G. Egloff,
E. S. R. E. Schaad, C. D. Lowry, Jr., Chem. Rev. 1931, 8, 1 – 80.
[3] a) M. S. Kharasch, P. C. White, F. R. Mayo, J. Org. Chem. 1938, 3, 33 – 47;b) M. S. Kharasch, W. Hered, F. R. Mayo, J. Org. Chem. 1941, 6, 818 – 829.
[4] H. Shaw, H. D. Perlmutter, C. Gu, S. D. Arcoo, T. O. Quibuyen, J. Org.
Chem. 1997, 62, 236 – 237.
[5] For a mechanistic study, see: a) D. D. Tanner, T. Pace, T. Ochiai, J. Am.
Chem. Soc. 1975, 97, 4303 – 4307; b) D. D. Tanner, T. C. S. Ruo, H. Takiguchi, A. Guillaume, Can. J. Chem. 1981, 59, 1368 – 1374. For bromination
using CBr4, see: c) Y. Nishina, B. Ohtani, K. Kikushima, Beilstein J. Org.
Chem. 2013, 9, 1663 – 1667.
[6] For selected recent reviews, see: a) T. Wirth, Microreactors in Organic
Synthesis and Catalysis, Wiley-VCH, Weinheim, 2013; b) V. Hessel, A.
Renken, J. C. Schouten, J. Yoshida, Micro Process Engineering, Wiley-VCH,
Weinheim, 2009; c) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R.

Chem. Eur. J. 2014, 20, 12750 – 12753

www.chemeurj.org

Bogdan, D. T. McQuade, Chem. Rev. 2007, 107, 2300 – 2318; d) T. Fukuyama, M. T. Rahman, M. Sato, I. Ryu, Synlett 2008, 151 – 163; e) D. Webb,
T. F. Jamison, Chem. Sci. 2010, 1, 675 – 680; f) S. Suga, D. Yamada, J.
Yoshida, Chem. Lett. 2010, 39, 404 – 406; g) J. Yoshida, H. Kim, A. Nagaki,
ChemSusChem 2011, 4, 331 – 340; h) J. Wegner, S. Ceylan, A. Kirschning,
Adv. Synth. Catal. 2012, 354, 17 – 57; i) S. V. Ley, Chem. Rec. 2012, 12,378 – 390; j) C. Wiles, P. Watts, Green Chem. 2012, 14, 38 – 54; k) D. T.
McQuade, P. H. Seeberger, J. Org. Chem. 2013, 78, 6384 – 6389; l) S. G.
Newman, K. F. Jensen, Green Chem. 2013, 15, 1456 – 1472.
[7] For recent work on photoreactions and microreactors, see; a) A. Sugimoto, T. Fukuyama, Y. Sumino, M. Takagi, I. Ryu, Tetrahedron 2009, 65,
1593 – 1598; b) K. Tsutsumi, K. Terao, H. Yamaguchi, S. Yoshimura, T. Morimoto, K. Kakiuchi, T. Fukuyama, I. Ryu, Chem. Lett. 2010, 39, 828 – 829;c) S. Fuse, N. Tanabe, M. Yoshida, H. Yoshida, T. Doi, T. Takahashi, Chem.
Commun. 2010, 46, 8722 – 8724; d) T. Fukuyama, Y. Kajihara, Y. Hino, I.
Ryu, J. Flow Chem. 2012, 1, 40 – 45; e) S. Aida, K. Terao, Y. Nishiyama, K.
Kakiuchi, M. Oelgemçller, Tetrahedron Lett. 2012, 53, 5578 – 5581. For
recent reviews, see; f) Y. Matsushita, T. Ichimura, N. Ohba, S. Kumada, K.
Sakeda, T. Suzuki, H. Tanibata, T. Murata, Pure Appl. Chem. 2007, 79,
1959 – 1968; g) M. Oelgemçller, Chem. Eng. Technol. 2012, 35, 1144 –1152.
[8] For flow fluorination by molecular fluorine, see: a) R. D. Chambers,
R. C. H. Spink, Chem. Commun. 1999, 883 – 884. For flow alkane chlorination by molecular chlorine or sulfuryl chloride, see: b) H. Matsubara, Y.
Hino, M. Tokizane, I. Ryu, Chem. Eng. J. 2011, 167, 567 – 571. For flow
benzyl chlorination by molecular chlorine, see: c) H. Ehrich, D. Linke, K.
Morgenschweis, M. Baerns, K. Jhnisch, Chimia 2002, 56, 647 – 653. For
reviews on flow halogenation, see: d) P. Lçb, H. Lçwe, V. Hessel, J. Fluorine Chem. 2004, 125, 1677 – 1694.
[9] For recent work on flow benzyl bromination, see: a) (HBr-H2O2) W. Yu,
D. Yu, M. Zheng, S. Shan, Y. Li, J. Gao, J. Chem. Res. 2012, 36, 258 – 260;b) (NBS) D. Šterk, M. Jukič, Z. Časar, Org. process Res. Dev. 2013, 17,
145 – 151; c) (NBS) D. Cantillo, O. de Frutos, J. A. Rincon, C. Mateos, C. O.
Kappe, J. Org. Chem. ASAP, DOI: 10.1021/jo402409k.
[10] Z.-H. Li, K.-N. Fan, M. W. Wong, J. Phys. Chem. A 2001, 105, 10890 –
10898.
[11] N. Leplat, A. Wokaun, M. J. Rossi, J. Phys. Chem. A 2013, 117, 11383 –
11402.
[12] a) J. Snell, A. Weissherger, Org. Synth. Coll. 1955, 3, 788; b) E. F. M. Stephenson, Org. Synth. Coll. 1963, 4, 984.
[13] a) A. Wohl, Ber. Dtsch. Chem. Ges. 1919, 52, 51 – 63; b) K. Ziegler, A.
Spath, E. Schaaf, W. Schumann, E. Winkelmann, Justus Liebigs Ann.
Chem. 1942, 551, 80 – 119; c) C. Djerassi, Chem. Rev. 1948, 43, 271 – 317.
[14] a) A. Amati, G. Dosualdo, L. H. Zhao, A. Bravo, F. Fontana, F. Minisci, H. R.
Bjorsvik, Org. Process Res. Dev. 1998, 2, 261 – 269; b) R. Mestres, J. Palenzuela, Green Chem. 2002, 4, 314 – 316.
[15] D. Kikuchi, S. Sakaguchi, Y. Ishii, J. Org. Chem. 1998, 63, 6023 – 6026.
[16] a) A. Ogawa, D. P. Curran, J. Org. Chem. 1997, 62, 450 – 451. Also, see reviews: b) J. J. Maul, P. J. Ostrowski, G. A. Ublacker, B. Linclau, D. P.
Curran, Top. Curr. Chem. 1999, 206, 79 – 105; c) H. Matsubara, I. Ryu, Top.
Curr. Chem. 2011, 308, 135 – 152.
[17] a) E. Leyva, M. S. Platz, G. Persy, J. Wirz, J. Am. Chem. Soc. 1986, 108,3783 – 3790; b) G. Dorman, G. D. Prestwich, Biochemistry 1994, 33,
5661 – 5673.
[18] K. Egusa, K. Fukase, S. Kusumoto, Synlett 1997, 675 – 676. 4-Azido-3chlorobenzyl bromide (5 g) can be purchased from Wako Pure Chemical
Industries, Ltd.

Received: February 21, 2014
Published online on August 29, 201412753

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