The halogenation of aliphatic C-H bonds with peracetic acid and halide salts

Article abstract of DOI:10.1055/s-0029-1219832

Hydrocarbons react with molar concentrations of peracetic acid and halide salts to yield predominantly monohalogenated products under optimum conditions, with chlorination being more oxidatively efficient than bromination. The alkane halogenation proceeds at ambient temperature and does not require a heavy-metal catalyst. The observed reactivity is consistent with a radical mechanism, in which the peracid initially reacts with the halide ions to yield halogen-atom radicals, which ultimately oxidize the hydrocarbon. Although the reactivity proceeds slightly more efficiently in acetonitrile, the halogenation protocol works well in water.

Full text of DOI:10.1055/s-0029-1219832

LETTER
1377
The Halogenation of Aliphatic C–H Bonds with Peracetic Acid and Halide
Salts
H
Y
alogenation of
A
u
liphatic
C
–H Bond
H
s
e, Christian R. Goldsmith*
Department of Chemistry & Biochemistry, Auburn University, Auburn, AL 36849, USA
Fax +1(334)8446959; E-mail: crg0005@auburn.edu
Received 3 February 2010
composes during storage.22 Furthermore, the analogous
Abstract: Hydrocarbons react with molar concentrations of perace-
tic acid and halide salts to yield predominantly monohalogenated
products under optimum conditions, with chlorination being more
bromination with iodobenzene dibromide has not been re-
II
ported. The transition-metal complex [Fe (TPA)Cl ]
2
oxidatively efficient than bromination. The alkane halogenation (TPA = tripicolylamine) uses tert-butylhydroperoxide
proceeds at ambient temperature and does not require a heavy-metal (TBHP) as a terminal oxidant to convert cyclohexane to
chlorocyclohexane.2
3,24
The chloride can be replaced by
catalyst. The observed reactivity is consistent with a radical mech-
anism, in which the peracid initially reacts with the halide ions to
yield halogen-atom radicals, which ultimately oxidize the hydrocar-
bon. Although the reactivity proceeds slightly more efficiently in
acetonitrile, the halogenation protocol works well in water.
23,24
bromide, resulting in bromination.
The iron-mediated
halogenation chemistry is stoichiometric with respect to
the metal complex; adding further equivalents of TBHP
leads to substrate oxygenation instead of halogenation.23
Key words: alkanes, oxidation, halogenation, free radicals, green
chemistry
O
OH
Cl
O
The direct conversion of aliphatic C–H bonds to more
useful functional groups is a topic of intense research.1
Compounds containing C–X bonds (X = Cl, Br), in partic-
ular, are synthetically versatile and represent valuable pre-
Et4NCl or NaCl, r.t.
–4
Scheme 1
cursors to more complex organic products due to their Reported here is a novel synthetic protocol capable of
5
–9
roles in C–C coupling reactions. Additionally, many converting nonactivated aliphatic C–H bonds to C–Cl and
natural products of pharmaceutical interest contain C–Cl C–Br functional groups. A mixture of peracetic acid (PA)
and C–Br functionalities; examples with antitumor activ- and a halide salt oxidizes cyclohexane to chloro- or bro-
ity include certain monoterpene derivatives and nostocy- mocyclohexane selectively, with only traces of higher-
1
0
clophanes. The installation of a halogen atom can order halogenation products observed under optimum
improve an organic molecule’s capability to enter cells conditions (Scheme 1). A previously reported method
and/or greatly impact the interaction with its biological uses meta-chloroperbenzoic acid (MCPBA) to perform
1
1
19
target, and the halogen functional groups may be essen- the same transformation at a lower yield. Our process
tial for the documented medicinal benefits of these natural has four benefits over most previously reported halogena-
products.
tion reactions.9
,25–27
First, PA is a relatively innocuous ter-
minal oxidant, particularly compared to the more
Much progress has been made recently towards the halo-
genation of aromatic C–H bonds, particularly with respect
9,27
commonly used Cl and Br .
Second, the halogen
2
2
source is a halide salt, as opposed to an elemental halogen
or a halogenated solvent, such as chloroform or carbon
tetrachloride.25 Third, the reported halogenation requires
neither high temperatures nor a heavy-metal catalyst to
proceed.26 Fourth, the PA-mediated halogenation can be
adapted to work in water. Despite the relatively mild con-
ditions, the reaction can activate strong aliphatic C–H
to finding more environmentally benign terminal oxidants
for the reactivity.12–18 Less advancement has been made in
the development of mild reactions capable of halogenat-
9
,12,19
ing aliphatic C–H bonds.
The procedure used most
commonly in industry is free-radical halogenation, in
which either Cl or Br serve as both terminal oxidant and
2
2
halogen source. The severe reactivity of Cl and Br com-
2
2
–1
groups, such as the 95–100 kcal mol bonds found in cy-
plicates their use as reagents. For chlorination, iodoben-
clohexane.28
zene dichloride (PhICl ) sometimes serves as an
2
1
5,20,21
alternative.
Upon irradiation, PhICl can chlorinate When treated with high concentrations of tetraethylam-
cyclohexane and toluene. One attractive benefit of monium chloride (TEACl) and PA in acetonitrile
2
2
0
PhICl is that it can be prepared from ionic chloride sourc- (MeCN), cyclohexane is converted into predominantly
2
es; however, it is unstable to light and heat and readily de- chlorocyclohexane, with traces of cyclohexanone and
negligible amounts of higher-order chlorinated products
when the substrate is present in excess of the oxidant
SYNLETT 2010, No. 9, pp 1377–1380
Advanced online publication: 15.04.2010
DOI: 10.1055/s-0029-1219832; Art ID: S00310ST
x
x.
x
x.
2
0
1
0
(
Table 1, Figure 1). When the concentration of oxidant
exceeds that of the substrate, polychlorinated products do
©
Georg Thieme Verlag Stuttgart · New York

1
378
Y. He, C. R. Goldsmith
LETTER
form (Table 2). With 1.32 M TEACl and 0.132 M PA, the the PA oxidizes cyclohexane to cyclohexanone instead of
oxidative efficiency of the chlorination is 72% (Table 1, the chlorinated product. At higher concentrations of chlo-
entry 5); the other terminal oxidants that were investigated ride, this oxygenated byproduct accounts for less than 1%
do not promote halogenation as efficiently. Reactions of the oxidized cyclohexane. Unlike the MCPBA-mediat-
19
with TBHP, H O , and iodosobenzene yield, at best, trace ed halogenation reported by Kojima et al., PA-promoted
2
2
quantities of chlorocyclohexane, as assessed by GC anal- chlorination is much more efficient than the analogous
ysis of the reaction mixtures. With 1.32 M TEACl and bromination. The PA-promoted bromination uses TEABr
0
.132 M of the peracid MCPBA, the oxidative efficiency as the halide source and has an optimum efficiency of just
is only 21% (Table 1, entry 4), consistent with the results 30%. The bromination reactions, however, generally yield
1
9
reported by Kojima et al.
less of the ketone byproduct.
The reaction also proceeds in water, albeit less efficiently.
The peak efficiencies are 59% for chlorination and 16%
for bromination (Table 1). The reduced oxidative effi-
ciency likely results from the immiscibility of the cyclo-
hexane substrate and water. There is precedence for
Table 1 Reactivity of Cyclohexanea
Entry Oxidant
Halide salt Halide
M]
Efficiency X/O
b
[
(%)
<1
<1
1.3
21
72
30
36
59f
16
0
ratio
1
2
3
4
H O
Et NCl
1.32
1.32
1.32
1.32
1.32
0.66
1.32
6.00
3.33
0
–c
2
2
4
aqueous halogenation reactions; a system involving H O2
2
t-BuO H
Et NCl
–c
and HBr was reported to brominate benzylic C–H
2
4
bonds.1
2,29
As with the protocol reported in this manu-
PhIO
MCPBA
PA
Et NCl
0.08
4.8
71
4
script, the halogenation chemistry of the H O –HBr sys-
2
2
Et NCl
tem proceeds at room temperature and does not require a
metal catalyst. However, neither the reactivity of the
H O –HBr mixture with more oxidatively robust alkanes
4
5
Et NCl
4
2
2
29
6d
nor attempts at chlorination were reported.
PA
Et NBr
93
16
56
4
7e
Anthracene, toluene, cyclohexene, and adamantane were
tested as alternate substrates for the chlorination reaction
in order to assess its regioselectivity and its tolerance for
olefins and aromatic C–H bonds (Table 2). Anthracene is
halogenated to a mixture of mono- and polychlorinated
products, demonstrating a second mode of reactivity. Un-
der the reaction conditions, acetyl hypochlorite could po-
PA
NaCl
NaCl
NaBr
8e
9e
0
PA
PA
–g
1
1
1
1
1
1
PA
Et NCl
–g
4
1
PA
Et NCl
0.132
0.266
0.667
1.32
1.98
2.64
56
58
62
72
63
40
4.1
5.7
4
+
tentially form and provide Cl for electrophilic aromatic
substitution reactions.3
0–32
Since toluene contains both
2
PA
Et NCl
4
benzylic and aromatic C–H bonds, it was selected as a
substrate in order to assess the relative speeds of the ali-
phatic and aromatic C–H halogenations. The products of
toluene chlorination are mostly chloromethylbenzenes,
and benzyl chloride accounts for only 5% of the oxidized
products (Table 2). The product distribution demonstrates
that the aromatic C–H halogenation proceeds more rapid-
ly than the aliphatic C–H oxidation. The investigation of
the aromatic C–H oxidation is ongoing in our laboratory.
3
PA
Et NCl
11
4
4
PA
Et NCl
71
114
109
4
5
PA
Et NCl
4
1
6
PA
Et NCl
4
a
Standard reaction conditions: 1.32 M cyclohexane, 0.132 M oxidant,
1
.8 mL total volume, 22 °C, 8 h.
Efficiency defined as percent yield based on the oxidant.
Trace amounts of cyclohexanol, cyclohexanone, and chlorocyclo-
b
c
Cyclohexene is oxidized to trans-1,2-dichlorocyclohex-
ane with TEACl as the halide source and trans-1,2-dibro-
mocyclohexane with TEABr as the halide source
(Table 2). The bromination reaction proceeds much more
cleanly than the chlorination, which yields several side
products, many of which are not readily identifiable. The
dihalogenated major products have previously been ob-
served in the oxidation of cyclohexene by Cl and Br .
hexane are present.
d
Concentration of oxidant is 0.264 M.
Water used as solvent. The pH during the reaction is 4.
An isolated yield of 28% is reported in the Supporting Information.
No oxygenated products observed.
e
f
g
The oxidative efficiency of the reaction depends on the
identity and concentration of the halide salt (Figure 1).
When no TEACl or tetraethylammonium bromide
2
2
Adamantane is oxidized to a mixture of 1- and 2-chloro-
adamantanes with a preference for the activation of the C–
H bonds on the tertiary carbons (Table 2). The observed
lack of regioselectivity for the chlorination of adamantane
is suggestive of a radical mechanism.
(
TEABr) is present, no oxidation occurs. The efficiency
increases with the concentration of TEACl until it reaches
0 equivalents relative to the oxidant. Above this ratio, the
1
yield of chlorocyclohexane decreases. The incidence of
cyclohexanone, the oxygenated byproduct, steadily de-
creases with increasing halide concentration. With 1
equivalent of chloride relative to oxidant, roughly 20% of
The color changes that accompany the halogenation reac-
tions are consistent with the presence Cl and Br in the
2
2
reactive mixture. During the chlorination reactions, the
Synlett 2010, No. 9, 1377–1380 © Thieme Stuttgart · New York

LETTER
Halogenation of Aliphatic C–H Bonds
1379
The observation of Cl and Br is intriguing since the re-
2
2
actions occur at room temperature and without a heavy-
metal catalyst. In the absence of hydrocarbon substrates,
this may represent an alternative to the Deacon process,
which uses high temperatures and a copper catalyst to pro-
33
duce Cl from chloride salts and dioxygen.
2
Although most halogenation reactions were run under am-
bient light, the chlorination of cyclohexane was also
found to proceed in the dark. During these latter reactions,
the solutions still turn green, suggesting that the reaction
between PA and the chloride salt is not initiated by pho-
tons. The oxidative efficiencies of the reactions run in the
dark are identical within error to those of reactions run un-
der ambient light.
One mechanistic possibility for the alkane oxidation is
that the peracid may initially convert the alkane to an al-
cohol, which would then undergo acid-catalyzed nucleo-
philic substitution to form the organohalide product.
Under the conditions used to convert cyclohexane to chlo-
rocyclohexane, cyclohexanol was converted into cyclo-
hexanone exclusively (Table 2). Additionally, the alcohol
was stable in a solution of acetic acid and TEACl at the
temperature and duration used for the experiments, pro-
viding further evidence that cyclohexanol is not a plausi-
ble intermediate for these reactions and that cyclohexane
is oxidized directly to chlorocyclohexane.
Figure 1 Dependence of the oxidative efficiencies for the formation
of chlorocyclohexane (red) and cyclohexanone (blue) on the concen-
tration of chloride, added in the form of TEACl. The starting concen-
tration of cyclohexane was 1.32 M, whereas the starting concentration
of peracetic acid was 0.132 M.
Table 2 Reactivity of Other Hydrocarbon Substratesa
Substrate
Efficiency Identified products
%)
(
9
,10-dichloranthracene (77%), anthro-
1
00
quinone (19%), 9,10-tetrachloro-
The lack of regioselectivity in the adamantane reactions
and the production of elemental halogens suggest the in-
9
,10-dihydroanthracene (4%)
1
-chloroadamantane (79%), 2-chloro- termediacy of halogen atom radicals. Based on the reduc-
2
4
4b
adamantane (21%)
tion potentials of the species involved, peracetic acid
0
34
(
E = 2.05 V vs. NHE) is thermodynamically capable of
chloromethylbenzenes (94%), benzyl
chloride (6%)
–
0
–
oxidizing Cl (Cl , E = 1.36 V vs. NHE) and Br (Br ,
6
2
2
0
E = 1.07 V vs. NHE) to chlorine and bromine radicals, re-
spectively.35 The PA is converted into acetate and water
during this process. The halogen-atom radicals are be-
lieved to be responsible for the abstraction of the hydro-
gen atom from the alkane. Similar chemistry was
proposed for the oxidation of enones and alkenes with ox-
one and sodium halides, although no aliphatic C–H acti-
OH
1
00
cyclohexanone (100%)
chlorocyclohexane (72%), cyclohex-
anone (7%)
44
d
3
6
1
3
,2-dichlorocyclohexane (21%),
-chlorocyclohexene (<1%)
vation was reported. When chlorination of cyclohexane
1
1
00
is attempted in the presence of BrCl C, bromocyclohex-
3
ane is observed as a side product, consistent with the in-
termediacy of a cyclohexyl radical.
1
3
,2-dibromocyclohexane (77%),
-bromocyclohexene (23%)
00c
The reliance of the halogenation chemistry on the initially
generated halogen atom radicals may explain the nonlin-
ear dependence of the oxidative efficiency on the halide
concentration. We hypothesize that at higher concentra-
tions of chloride, the elevated production of Cl radicals fa-
a
Standard reaction conditions: 0.050 M substrate, 0.50 M TEACl,
.20 M PA in 10 mL MeCN, 22 °C, 8 h.
0
b
CH Cl used instead of MeCN. An isolated yield of 20% is reported
2
2
in the Supporting Information.
c
0
.5 M TEABr used instead of TEACl.
cilitates the formation of Cl . The conversion of Cl
2
d
Dichlorocyclohexanes account for the remainder of the product.
radicals to gaseous Cl removes the oxidant from the reac-
2
tion mixture, thereby reducing the oxidative efficiency of
alkane halogenation. The greater overpotential for the ox-
idation of bromide relative to chloride would hasten the
production of bromine radicals relative to chloride radi-
cals. Consequently, more of the bromide may be diverted
solution turns faint green before fading to pale yellow;
this color completely disappears when the reaction is put
under reduced pressure, consistent with the loss of dis-
solved chlorine gas. During bromination, the solution
turns brownish orange, suggesting the presence of Br2.
Kojima et al. observed similar spectral features in the pre-
viously reported halogenation reactions with MCPBA.19
into Br production instead of alkane halogenation, ex-
2
Synlett 2010, No. 9, 1377–1380 © Thieme Stuttgart · New York

1
380
Y. He, C. R. Goldsmith
LETTER
plaining the lower oxidative efficiency of PA-mediated References and Notes
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(
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protocol can be adapted to work in water, with NaCl or
NaBr as the halogen source. The incidence of side prod-
ucts can be modulated and minimized by adjusting the
concentrations of oxidant and halide. The major drawback
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the dihalogenation of alkenes proceed much more quickly
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2
3
4
2
2
iodosobenzene (PhIO), PA (32% in AcOH), TBHP, H O , and
2
2
(
(
(
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1
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Acknowledgement
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