Visible Light-Induced Oxidative Chlorination of Alkyl sp3 C-H Bonds with NaCl/Oxone at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.7b02153

A visible light-induced monochlorination of cyclohexane with sodium chloride (5:1) has been successfully accomplished to afford chlorocyclohexane in excellent yield by using Oxone as the oxidant in H₂O/CF₃CH₂OH at room temperature. Other secondary and primary alkyl sp³ C-H bonds of cycloalkanes and functional branch/linear alkanes can also be chlorinated, respectively, under similar conditions. The selection of a suitable organic solvent is crucial in these efficient radical chlorinations of alkanes in two-phase solutions. It is studied further by the achievement of high chemoselectivity in the chlorination of the benzyl sp³ C-H bond or the aryl sp² C-H bond of toluene.

Full text of DOI:10.1021/acs.orglett.7b02153

Letter
pubs.acs.org/OrgLett
Visible Light-Induced Oxidative Chlorination of Alkyl sp3 C−H Bonds
with NaCl/Oxone at Room Temperature
Mengdi Zhao and Wenjun Lu*
Department of Chemistry, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People’s Republic of China
S
* Supporting Information
ABSTRACT: A visible light-induced monochlorination of cyclohexane
with sodium chloride (5:1) has been successfully accomplished to afford
chlorocyclohexane in excellent yield by using Oxone as the oxidant in H2O/
CF3CH2OH at room temperature. Other secondary and primary alkyl sp3
C−H bonds of cycloalkanes and functional branch/linear alkanes can also
be chlorinated, respectively, under similar conditions. The selection of a suitable organic solvent is crucial in these efficient radical
chlorinations of alkanes in two-phase solutions. It is studied further by the achievement of high chemoselectivity in the
chlorination of the benzyl sp3 C−H bond or the aryl sp2 C−H bond of toluene.
lkyl sp3C−H bonds are inert, and it is very difficult to
construct new alkyl C−C, C−O, or C−N bonds directly
Scheme 1. Monochlorination of Cyclohexane at Room
Temperature
A
under mild conditions, which are usually prefunctionalized to
alkyl sp3C−halo bonds (halo = Cl, Br, I) in current synthetic
chemistry.1 Therefore, halogenation such as chlorination is still
one of the most popular methods in the first functionalization
of normal alkanes. Radical chlorination of alkyl sp3C−H bonds
with chlorine gas Cl2 is an effective and traditional way to
produce alkyl chlorides.2 However, there are two unsolved
problems in this chlorination. First, the maximum yield of alkyl
chloride based on chlorine is only 50% with equivalent HCl
formed as a byproduct during this redox reaction. Second, Cl2 is
a very toxic gas as the chlorine source, which is inconvenient
and unsafe in operation, especially in laboratories. In the past
seven decades, to enhance the mass efficiency of chlorine and
the reaction performance, a lot of chlorine reagents at high
oxidation state were successfully developed to replace chlorine
gas in the chlorination of alkanes.3 For example, most recently,
it was disclosed that monochlorination of cyclohexane with
NaClO (3:1) could generate chlorocyclohexane in 93% yield in
the presence of a catalytic base-resistant porphyrin metal−
organic framework, PCN-602 in acetone/H2O at room
temperature (Scheme 1A).3f Actually, the most common
chlorine source is sodium chloride NaCl, a stable and not
risky solid, which is also a major feedstock for producing Cl2
and chlorine compounds in industry. However, an external
oxidant is necessary when NaCl is employed directly as chlorine
source in the chlorination of alkanes. Although some progress
was made on the NaCl/oxidant system in oxidative
chlorinations,4 alkyl chloride such as chlorocyclohexane was
not generated in a good yield under mild conditions (Scheme
1B).4c Herein, we report an effective monochlorination of
alkanes with NaCl/Oxone under irradiation of visible light at
room temperature. For example, chlorocyclohexane was
produced in 99% yield based on NaCl in this reaction, which
is the highest one reported so far (Scheme 1C).
Oxone is a stable, nontoxic, and inexpensive triple salt
(2KHSO5·KHSO4·K2SO4), which is applied widely as an
Received: July 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oxidant in chemical reactions.5 An early example of the
application of NaCl/Oxone as the chlorine source/oxidant was
an oxidative chlorination of benzylic sp2 C−H bonds of toluene
at reflux temperature in 1960.4a Since then many reports have
been found in the chlorination of arenes, benzylic groups, and
β-dicarbonyl compounds by using NaCl/Oxone or KCl/
Oxone.6 It was assumed that chlorine could be generated in
situ by oxidation of Cl− with Oxone in these reactions. Thus, we
speculated it was feasible that the combination of radical
chlorination under irradiation and oxidation of chlorine ions
together give a new chlorination of inert alkyl sp3 C−H bonds
with NaCl/Oxone under mild conditions (Scheme 1D).
To enhance the yield of chlorocyclohexane 2a in the
monochlorination of cyclohexane 1a with NaCl/Oxone, the
reaction conditions were investigated, as shown in Table 1.
identical conditions. It means that the mass efficiency of NaCl
is close to 100% in this reaction (entry 11). After optimization
(see Supporting Information (SI)), 2a was obtained in 93%
isolated yield just using 0.8 equiv of Oxone in 1 h (entry 12). In
contrast, in H2O/benzene, the yield was 69% (entry 14). It
seems that the radical chlorination of cyclohexane prefers a
polar organic solvent miscible with water though it also
proceeds smoothly in a nonpolar solvent, even in the absence
of external organic solvent under mild conditions (entries 11−
15). According to our observation, in the case of H2O/TFE as
the solvent, there were two liquid phases during the
chlorination. One was the nonpolar substrate 1a with chlorine,
another was the polar H2O/TFE solvent itself containing most
products 2a, NaCl, Oxone, etc. The separation of substrate and
product by solvent is beneficial to the reaction rate and
selectivity.
Chlorination of various inert alkyl sp3 C−H bonds was
screened further, and the results are listed in Scheme 2. The
reaction conditions for chlorination of 1a were still available to
other nonpolar cycloalkanes such as cyclopentane 1b and
cyclopentane 1c. In H2O/TFE, the yields of monochloride
Table 1. Chlorination of Cyclohexane with NaCl/Oxone
a
under Irradiation by Visible Light at Room Temperature
a
Scheme 2. Chlorination of Inert Alkyl sp3 C−H Bonds
b
entry
1a (equiv)
solvent
2a yield (%)
1
2
1
1
1
1
1
1
1
2
3
4
5
5
1
5
5
1
40
40
4
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
TFE
c
3
d
4
0
5
43
50
60
75
78
83
99
99(93)
53
69
66
55
6
7
8
TFE
9
TFE
10
11
TFE
TFE
e
12
TFE
13
14
15
benzene
benzene
f
16
TFE
a
Reaction conditions: cyclohexane 1a (0.25−1.25 mmol, 1−5 equiv),
NaCl (0.25 mmol, 1 equiv), Oxone (0.25 mmol, 1 equiv), H2O (0.09
mL), solvent (0.2 mL), 11 W CFL, air, rt, 8 h (entries 12−14, 1 h).
b
1
Yields are based on NaCl and detected by H NMR analysis using
c
CH2Br2 as an internal standard and isolated yield in parentheses. In
the dark. Without NaCl. Oxone (0.20 mmol, 0.8 equiv). NaCl (2
d
e
f
equiv), Oxone (0.8 equiv), 1 h, yield based on 1a.
Initially, 1a, NaCl and Oxone (1:1:1) were used to undergo the
chlorination in H2O/CHCl3 or only in H2O under irradiation
by 11 W CFL (compact fluorescent lamp) at room temper-
1
ature. Fortunately, 40% yield of 2a was detected by H NMR
analysis after 8 h (Table 1, entries 1 and 2). In the dark,
however, the yield was only 4%, indicating that it was a visible
light-induced radical chlorination (entry 3). Without NaCl
added, 2a was not generated, implying NaCl was the only
chlorine source in the reaction (entry 4). Then, other organic
solvents were tested including CH2Cl2, CH3CN, CF3CH2OH
(TFE), etc. (entries 5−7). Interestingly, in H2O/TFE, the yield
could be up to 60% based on either 1a or NaCl (1a/NaCl =
1:1) (entry 7). With the amount of 1a increasing, 2a was also
produced much more (entries 7−11). When 5 equiv of 1a was
employed, the yield of 2a was 99% based on NaCl under the
a
Reaction conditions: substrate 1 (0.25−1.25 mmol, 1−6 equiv),
NaCl (1 equiv), Oxone (0.8−1 equiv), H2O (0.09 mL), solvent (0.2
mL), 11 W CFL, air, rt, 1−4 h. Yields are based on NaCl and detected
by H NMR analysis using CH2Br2 as an internal standard.
1
B
DOI: 10.1021/acs.orglett.7b02153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
products 2b and 2c were also close to 100% based on NaCl
when cycloalkanes were used in excess. Since there were both
secondary and more active tertiary sp3 C−H bonds on
nonpolar and solid adamantane 1d, two monochloride isomers
2d were generated in a moderate yield in H2O/benzene. If the
functional compounds 1e−1i as polar substrates contain only
one kind of primary sp3 C−H bond, their oxidative
chlorinations would proceed very well. For example, when a
tert-butyl group was connected directly to a functional group
such as −Ph, −CN, −CO2H, or −Cl, the monochlorides 2e−
2h could be obtained in ∼90% yield by using excess substrates
in H2O/CHCl3 under similar conditions (see SI). For liner
alkanes with functional groups 1j−1m including nitroalkane,
ester, and carboxylic acid, the total yields of monochlorides 2j−
2m based on NaCl were good in H2O/CHCl3, but isomers
could not be avoided, and the product distribution depended
on the reactivity of the sp3 C−H bond in the radical
chlorination. In these alkanes bearing electron-withdrawing
groups, the remote sp3 C−H bonds were attacked more easily
by radicals even though they were primary ones. For nonpolar
liner alkanes such as hexane 1n, H2O/TFE was selected as the
solvent like in the cases of nonpolar cycloalkanes. However, the
isomer mixture 2n was found in a yield of 67% when 5 equiv of
1n underwent the chlorination with 1 equiv of NaCl/Oxone
under irradiation by 11 W CFL at room temperature.
was formed quickly under irradiation by 23 W CFL under the
same conditions (Table 2, entries 1 and 2). It means that a light
source is necessary in the radical chlorination of sp3C−H
bonds, like in the case of 1a. Otherwise, chlorination is
dominated by electrophilic aromatic substitution (EAS) in the
presence of NaCl/Oxone as the chlorine source in H2O at
room temperature. When CHCl3 or benzene was added into
the solution, radical chlorination on benzyl sp3 C−H bonds
could proceed mainly in the phase of 3a/organic solvent under
light. Meanwhile, in this aprotic solvent, electrophilic
chlorination of aryl sp2 C−H bonds hardly occurred (entries
3−6). Thus, under the certain conditions, 4a was obtained in
57% yield in H2O/benzene (entry 7).3g As shown in Scheme 2,
alkyl chloride 2e was also generated as the sole product through
the radical reaction in H2O/CHCl3 even though the alkyl sp3
C−H bonds of tert-butylbenzene 1e were more inert than
normal benzyl sp2C−H bonds. In contrast, when a protic
solvent such as TFA (CF3CO2H) or TFE was used to polarize
chlorine to Clδ+Clδ−,6b,d an electrophilic chlorination of aryl sp2
C−H bonds was the only effective reaction no matter whether
under light or in the dark, and the isolated yield of 5a could be
up to 98% (entries 8−11). However, as mentioned above, in
the chlorination of cyclohexane 1a, most of its monochloride
product 2a was in the solvent of H2O/TFE with Clδ+Clδ−, not
in the phase of nonpolar substrate 1a with Cl2. It was not only
to avoid the formation of dichloride byproduct from 2a but also
to accelerate the radical chlorination of 1a to afford 2a in both
high yield and selectivity.
In the above oxidative chlorinations of inert alkyl sp3 C−H
bonds, the selection of organic solvent is very important. Three
organic solvents including TFE, benzene, and chloroform
(CHCl3) were used very well with water. Effects of solvent on
the radical chlorination were studied further. Since toluene 3a
has both active benzyl sp3 C−H bonds and aryl sp2 C−H
bonds, its chlorinations were investigated in this oxidative and
visible light-induced reaction system under different conditions,
especially in various organic solvents, and the results are listed
in Table 2. Without any organic solvents, chlorotoluene 5a was
the major products in the dark, but benzyl monochloride 4a
Furthermore, the effects of solvent were also confirmed by
the chlorination of ethylbenzene 3b, including a radical reaction
in H2O/CHCl3 under visible light and an electrophilic
substitution in H2O/TFE, respectively (Scheme 3). However,
Scheme 3. Chlorination of Benzyl sp3 C−H Bonds vs Aryl
a
sp2 C−H Bonds
a
Table 2. Effects of Organic Solvent on Chlorination
entry
solvent
hv (CFL, W) conv (%) 4a (%) 5a (%) (o/p)
1
2
3
4
5
6
54
57
11
27
52
40
7
46 (31:15)
20 (13:7)
6 (2:4)
<1
23
32
5
CHCl3
CHCl3
CHCl3
benzene
benzene
CHCl3
TFE
a
Reaction conditions: substrate 3b−3d (0.25 mmol, 1 equiv), NaCl (1
15
23
23
23
23
23
26
34
39
57
0
b
equiv), Oxone (0.8 equiv), H2O (0.09 mL), solvent (0.2 mL), under
hv (23 W CFL) or in the dark, air, 2.5−8 h. Yields are based on the
substrate and detected by 1H NMR analysis using CH2Br2 as an
internal standard. Isolated yield. NaCl (2 equiv), Oxone (1.5 equiv),
18 h.
<1
0
c
7
65
69
87
87
98
0
b
c
d
8
69 (42:27)
87 (53:34)
87 (53:34)
98 (59:39)
9
0
10
TFE
0
e
11
TFE
0
a very electron-rich p-methoxy toluene 3c just underwent an
electrophilic chlorination of its aryl sp2 C−H bonds, but an
electron-deficient p-nitro toluene 3d was chlorinated exclusively
at its benzyl sp3 C−H bonds through a radical process. In the
cases of 3c and 3d, the reaction conditions just influenced the
product yield, not the selectivity.
a
Reaction conditions: toluene 3a (0.25 mmol, 1 equiv), NaCl (1
equiv), Oxone (0.5 equiv), H2O (0.09 mL), solvent (0.2 mL), air, rt, 4
h. Yields are based on 3a and detected by H NMR analysis using
CH2Br2 as an internal standard. Benzyl oxides such as benzoic acid
detected. NaCl (2 equiv), Oxone (1 equiv), 2.5 h. CF3CO2H (4
1
b
c
d
e
equiv) instead of H2O. Oxone (0.6 equiv), 5a isolated yield.
C
DOI: 10.1021/acs.orglett.7b02153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) (a) Dieter, R. K.; Nice, L. E.; Velu, S. E. Tetrahedron Lett. 1996,
37, 2377−2380. (b) Tamhankar, B. V.; Desai, U. V.; Mane, R. B.;
Wadgaonkar, P. P.; Bedekar, A. V. Synth. Commun. 2001, 31, 2021−
2027. (c) Takada, Y.; Hanyu, M.; Nagatsu, K.; Fukumura, T. J. Labelled
In summary, we have developed a very convenient method to
prepare alkyl chlorides in moderate to excellent yields, which is
an oxidative monochlorination of inert alkyl sp3 C−H bonds of
simple cycloalkanes and branch/linear functional alkanes with
NaCl/Oxone in H2O/TFE, H2O/CHCl3, or H2O/benzene
under visible light at room temperature. Although the effects of
organic solvent have been investigated on these chlorination
reactions in two-phase solutions, further studies on the reaction
mechanism, scope, and application are underway.
Compd. Radiopharm. 2012, 55, 383−386. (d) C
̧
imen, Y.; Akyuz, S.;
̈
Turk, H. New J. Chem. 2015, 39, 3894−3899.
̈
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02153.
Typical experimental procedures, detailed screening of
the reaction conditions, preparations, and character-
ization of compounds, and spectroscopic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: luwj@sjtu.edu.cn.
ORCID
Wenjun Lu: 0000-0001-8077-7060
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Grant No. 21372153) for financial support.
REFERENCES
(1) (a) Lin, R.; Amrute, A. P.; Per
117, 4182−4247. (b) Kozlowski, M. C. Acc. Chem. Res. 2017, 50, 638−
643. (c) Lu, W.; Zhou, L. Oxidation of C−H Bonds; John Wiley &
Sons, Inc.: Hoboken, NJ, 2017.
■
́
ez-Ramírez, J. Chem. Rev. 2017,
(2) (a) Kharasch, M. S.; Berkman, M. G. J. Org. Chem. 1941, 6, 810−
817. (b) Olah, G. A.; Schilling, P.; Renner, R.; Kerekes, I. J. Org. Chem.
1974, 39, 3472−3478. (c) Fletcher, B.; Suleman, N. K.; Tanko, J. M. J.
Am. Chem. Soc. 1998, 120, 11839−11845. (d) Sun, N.; Klabunde, K. J.
J. Am. Chem. Soc. 1999, 121, 5587−5588. (e) Matsubara, H.; Hino, Y.;
Tokizane, M.; Ryu, I. Chem. Eng. J. 2011, 167, 567−571.
(3) (a) Walling, C.; Jacknow, B. B. J. Am. Chem. Soc. 1960, 82, 6108−
6112. (b) Walling, C.; Jacknow, B. B. J. Am. Chem. Soc. 1960, 82,
6113−6115. (c) Banks, D. F.; Huyser, E. S.; Kleinberg, J. J. Org. Chem.
1964, 29, 3692−3693. (d) Fonouni, H. E.; Krishnan, S.; Kuhn, D. G.;
Hamilton, G. A. J. Am. Chem. Soc. 1983, 105, 7672−7676. (e) Quinn,
R. K.; Konst, Z. A.; Michalak, S. E.; Schmidt, Y.; Szklarski, A. R.;
̈
Flores, A. R.; Nam, S.; Horne, D. A.; Vanderwal, C. D.; Alexanian, E. J.
J. Am. Chem. Soc. 2016, 138, 696−702. (f) Lv, X.-L.; Wang, K.; Wang,
B.; Su, J.; Zou, X.; Xie, Y.; Li, J.-R.; Zhou, H.-C. J. Am. Chem. Soc.
2017, 139, 211−217. (g) Combe, S. H.; Hosseini, A.; Parra, A.;
Schreiner, P. R. J. Org. Chem. 2017, 82, 2407−2413. (h) Ozawa, J.;
Kanai, M. Org. Lett. 2017, 19, 1430−1433.
(4) (a) Kennedy, R.; Stock, A. M. J. Org. Chem. 1960, 25, 1901−
1906. (b) Hill, C. L.; Smegal, J. A.; Henly, T. J. J. Org. Chem. 1983, 48,
3277−3281. (c) Kojima, T.; Matsuo, H.; Matsuda, Y. Chem. Lett. 1998,
27, 1085−1086. (d) He, Y.; Goldsmith, C. R. Synlett 2010, 2010,
1377−1380.
(5) (a) Hussain, H.; Green, I. R.; Ahmed, I. Chem. Rev. 2013, 113,
3329−3371. (b) Ghanbari, F.; Moradi, M. Chem. Eng. J. 2017, 310,
41−62.
D
DOI: 10.1021/acs.orglett.7b02153
Org. Lett. XXXX, XXX, XXX−XXX