Photocatalytic Oxidative Bromination of Electron-Rich Arenes and Heteroarenes by Anthraquinone

Article abstract of DOI:10.1002/adsc.201701276

The estimated excited oxidation potential of sodium anthraquinone-2-sulfonate (SAS) increases from 1.8 V to about 2.3 V vs SCE by protonation with Br?nsted acids. This increased photooxidation power of protonated anthraquinone was used for the regio-selective oxidative bromination of electron rich (hetero)arenes and drugs in good yield. The mild reaction conditions are compatible with many functional groups, such as double and triple bonds, ketones, amides and amines, hydroxyl groups, carboxylic acids and carbamates. Mechanistic investigations indicate the photooxidation of the arene followed by nucleophilic bromide addition as the likely pathway. (Figure presented.).

Full text of DOI:10.1002/adsc.201701276

Title: Photocatalytic oxidative bromination of electron-rich arenes and
heteroarenes by anthraquinone
Authors: Daniel Petzold and Burkhard König
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701276
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10.1002/adsc.201701276
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Photocatalytic oxidative bromination of electron-rich arenes
and heteroarenes by anthraquinone
Daniel Petzolda and Burkhard Königa*
a
Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, Germany
* Fax: (+49)-941-943-1717. Phone: (+49)-941-943-4575. E-mail: Burkhard.Koenig@chemie.uni-regensburg.de
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
oxidation potential have not been developed yet or
require multistep syntheses.[3]
Abstract. The estimated excited oxidation potential of
sodium anthraquinone-2-sulfonate (SAS) increases from
1.8 V to about 2.3 V vs SCE by protonation with Brønsted
acids. This increased photooxidation power of protonated
anthraquinone was used for the regio-selective oxidative
bromination of electron rich (hetero)arenes and drugs in
good yield. The mild reaction conditions are compatible
with many functional groups, such as double and triple
bonds, ketones, amides and amines, hydroxyl groups,
carboxylic acids and carbamates. Mechanistic
investigations indicate the photooxidation of the arene
followed by nucleophilic bromide addition as the likely
pathway.
To enable the photo-oxidation of arenes and
heteroarenes with easily available photocatalysts, we
envisioned enhancing the oxidative power of
anthraquinones by protonation.[2] The applicability of
this approach was demonstrated by the photocatalytic
bromination of electron-rich arenes.[4] Employing
sodium anthraquinone sulfonate (SAS) as the
photocatalyst, sodium bromide as bromine source and
oxygen as terminal oxidant allows an efficient and
selective bromination of aromatic substrates with
oxidation potentials up to 2.3 V vs. SCE.[5] The excited
state oxidation potential of SAS was estimated from
electrochemical and spectroscopic data.[6] The
interaction of arenes with the SAS excited state was
confirmed by fluorescence quenching studies.[7]
Furthermore, the viability of this method for late-stage
functionalization of complex, bioactive molecules was
demonstrated.[8]
Keywords: photocatalysis, protonation, proton coupled
electron transfer, halogenation, oxidation
INTRODUCTION
The development of novel, photocatalytic
transformations received tremendous attention in the
past decade due to the versatile reactivity of radical
intermediates.[1] To form radicals, a single electron
transfer step is necessary.[1] However, direct single
electron oxidation or reduction of many substrates is
thermodynamically not feasible by the currently
available photocatalysts. Proton coupled electron
transfer (PCET) extends the accessible range, as the
interaction with acids or bases alters the oxidation or
reduction potential of carbonyl compounds, amides
and other substances up to 500 mV.[2]
However, PCET activation of aromatic C-H bonds
is difficult to realize, because they cannot be polarized
by simple bases. Thus, the direct photocatalytic
activation of aromatic C-H bonds is still challenging
and requires photocatalysts with a high oxidation
potential. Commonly used photocatalysts for these
processes are [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (EOx ≈ +
1.2-1.7 V) and acridinium based dyes (EOx ≈ + 2.0
V).[1] Photocatalysts offering a significantly higher
RESULTS AND DISCUSSION
Synthesis We started our investigations using anisole
(1) as a model substrate, sodium anthraquinone
sulfonate as the catalyst, two equivalents of acetic acid
(pKa = 4.76) to activate the anthraquinone derivative
and five equivalents of sodium bromide in a mixture
of acetonitrile and demineralized water (4:1) under air
atmosphere. Irradiation at 445 nm by a single LED for
18 h gave 43% conversion to the corresponding
brominated anisole derivative (2) (Table 1, entry 1).
As an increase of the amount of the acid did not
improve the yield significantly (entry 2), different
acids were tested (entries 3-4). The amount of
converted starting material increased with the strength
of the corresponding acid. Employing KHSO4 (pKa =
2.1) gave 80% conversion and changing to TFA (pKa
= 0.2) lead to full conversion. After more optimization
steps, the best conditions were identified, using 2
1
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10.1002/adsc.201701276
Advanced Synthesis & Catalysis
equiv. of NaBr, 2 equiv. of TFA and 5 mol% of
catalyst in a mixture of MeCN H2O 1:1 at 400 nm
irradiation, giving full conversion of the starting
material within 4 h (entry 5). Especially the change of
the light source from 445 nm to 400 nm greatly
accelerated the reaction due to the greater extinction
coefficient of the catalyst at shorter wavelengths (see
Fig. S1). Moreover, control experiments revealed that
in absence of acid, catalyst, light and/or air no reaction
took place (entries 6-8).
selectivity of the bromination. Electron-deficient
indole derivative 16 gave a moderate yield, as well as
the electron-rich benzimidazole derivative 17. Notably,
SAS could oxidize pyrazole 18 and its derivatives 19
and 20 to give the brominated compounds in excellent
yields. This extends recent observations, in which
pyrazole (EOx = 2.21 V vs SCE)[5] was shown to be
inert towards the oxidation by acridinium dyes and
used as a nucleophile in amination reactions instead. [3,
9] Finally, also bioactive compounds were brominated.
The painkillers phenazone (21) and tramadol (22) gave
excellent yields of only a single brominated product
and the complex alkaloid strychnine (23) could be
selectively brominated in moderate yield. The
hypolipidemic agent gemfibrozil (24) and the
anesthetic lidocaine (25) gave moderate yields due to
a competing oxidation of the benzylic position to the
corresponding aldehyde.[10] The reaction of the
benzylic position could be exploited for toluene (30)
(EOx = 2.2 V vs SCE)[4a] if persulfate was used as
sacrificial oxidant under inert atmosphere. In this case,
it was possible to achieve exclusive bromination of the
benzylic position in good yield. Unfortunately,
benzene (26) and electron-poor benzene derivatives
27-29 did not give any brominated products due to the
required high oxidation potentials.[5]
Table 1. Optimization of the reaction conditions.
Entry
SAS
[mol%]
Acid
[equiv.]
NaBr
Yield of
[equiv.] 2a)
1
20
20
20
20
5
AcOH [2]
AcOH [5]
KHSO4 [2]
TFA [2]
TFA [2]
-
5
5
5
5
2
2
2
2
2
43
2
50
3
80
4
100
100
n.r.
n.r.
n.r.
traces
5b)
6b)
7b)
8c)
9d)
5
-
TFA [2]
TFA [2]
TFA [2]
5
5
Scheme 1. Benzylic bromination of toluene. Conditions: 0.1
mmol of toluene, 5 mol% of SAS, 2 equiv. of TFA, K2S2O8
and NaBr respectively were in dissolved in 1 mL of MeCN
H2O 1:1 and irradiated at 400 nm for 4 h. a: Yield
determined by H-NMR using dimethyl sulfone as internal
standard.
General conditions: 0.1 mmol of anisole, indicated amount
of SAS, acid and NaBr in 1 mL of MeCN H2O 4:1, 18 h
irradiation at 445 nm. a) Yield determined by GC-FID using
naphthalene as internal standard. b) MeCN H2O 1:1 and 400
c)
d)
nm irradiation was used. MeCN H2O 1:1 but no light.
MeCN H2O 1:1, 400 nm irradiation under nitrogen
atmosphere. n.r. no reaction.
Mechanistic Investigations To get insight into the
mechanism, cyclovoltammetric and spectroscopic
investigations were performed. Cyclovoltammetry
revealed a ground state reduction potential of -0.56 V
vs. SCE for SAS in MeCN H2O 1:1 (see Fig. S2).
Addition of TFA to this solution showed a tremendous
impact by lowering the required potential by 0.55 V to
merely -0.01 V vs. SCE. We propose that the reduction
is facilitated by protonation in the presence of TFA
(see Fig. S2).[11] This shift of the ground state reduction
potential leads to a significant increase of the excited
state oxidation potential by approximately the same
voltage from 1.76 V to 2.3 V vs SCE (see Fig. S3) and
explains why TFA is required to successfully oxidize
In the next step, the synthetic scope of the
photocatalytic oxidative bromination was explored
(Fig. 1). All tested methoxy arenes showed full
conversion and good isolated yields (2-10). Moreover,
despite the acidic environment, Boc-protected amine
12 was isolated in good yield. On the other hand, the
electron withdrawing substituent in compound 13
reduces its reactivity in the reaction significantly.
Interestingly, amide 14 gave only the displayed
brominated product despite the presence of two
electron-donating groups at the second aromatic ring.
This indicates that also steric factors influence the
2
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10.1002/adsc.201701276
Advanced Synthesis & Catalysis
anisole (EOx = 1.81 V vs. SCE). To support this
hypothesis, control experiments using substrates with
3
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10.1002/adsc.201701276
Advanced Synthesis & Catalysis
Figure 1. General conditions: 0.1 mmol of substrate, 5 mol% of SAS, 2 equiv. of TFA and 2 equiv. of NaBr were dissolved
in 1 mL of MeCN H2O 1:1 and irradiated at 400 nm for 4 h. Given yields are isolated yields. a: Yield determined by GC-
FID calibration using naphthalene as internal standard. b: An oxygen balloon was connected to the vial through the septum.
c: Yield determined by H-NMR using dimethyl sulfone as internal standard. d: mixture of isomers at pyrazole position 4
and 5, ratio C4:C5 6:4. e: 4 equiv. of TFA were used.
compounds show non-linear quenching, which might
indicate a ground state pre-orientation via π-stacking
between the substrates and SAS. On the other hand,
TFA showed no significant quenching at all as well as
benzene, which has an oxidation potential of 2.48 V vs
SCE.[13] This observation is in good agreement with the
estimated oxidation potential of SAS and the
experimental findings, because benzene did not react
under our bromination conditions. Moreover, sodium
bromide showed similar quenching compared to
anisole and 1,3 DMB at low quencher concentrations
(Fig. 2 A). However, the formation of elemental
bromine was not observed during the reaction or
without substrate present (vide infra). This indicates
that bromide is not oxidized by SAS and only engages
a low oxidation potential were performed. The
experiments revealed that the bromination was also
possible without TFA present. 1,3,5-Trimethoxy-
benzene (EOx = 1.4 V vs. SCE)[4a] and 2-
methoxynapthalene (EOx = 1.5 V vs. SCE)[4a] gave the
corresponding brominated products, but at a much
slower rate and in lower yield indicating that the PCET
increases the driving force of the reaction significantly.
To investigate the interaction between the excited
photocatalyst and the substrate, emission quenching
experiments were performed. We found that anisole
and the more electron rich 1,3 dimethoxybenzene (1,3
DMB) are efficient quenchers, whereas N-
methylpyrazole is a moderate quencher of the delayed
fluorescence of SAS (Fig. 2 A).[12] Notably, all three
4
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10.1002/adsc.201701276
Advanced Synthesis & Catalysis
1,3 DMB
8
A
I0/I
B
anisole
pure SAS
7
6
5
4
3
2
1
0
N-methypyrazole
NaBr
SAS + 10 µL 1,3 DMB
SAS + 20 µL 1,3 DMB
OD
2
1
0
benzene
TFA
0
10
20
30
40
50
300
350
400
450
[Q]/mM
λ/nm
Figure 2. A: Stern-Volmer quenching plot of different substrates and additives. The oxidation potentials of TFA and
benzene are too high to quench the catalyst whereas 1,3 DMB, anisole and N-methylpyrazole are good/moderate quenchers.
Sodium bromide also shows moderate quenching of the catalyst, which can be attributed to the intermolecular heavy atom
quenching effect.[14] B: UV-VIS absorption spectra of pure SAS and after addition of different amounts of 1,3 DMB.[15]
Figure 3. Proposed mechanism for the photocatalytic bromination of arenes and heteroarenes yielding exclusively mono-
brominated compounds.
SAS-H+*. This intermediate oxidizes the arene and the
in intermolecular heavy atom fluorescence
quenching.[14] Next, we investigated the ground state
interactions between the catalyst and the other reaction
components by UV-VIS spectroscopy. No significant
change of the spectrum was observed by addition of
NaBr or TFA (not shown). However, a small,
concentration dependent change of the SAS spectrum
could be observed after addition of 1,3 DMB to the
catalyst (Fig. 2 B).[15] The reason for the shift might be
π-stacking of the non-polar anthraquinone core and 1,3
DMB in the polar solvent mixture rather than the
formation of a charge transfer complex. This potential
pre-orientation of substrate and catalyst might also
play a role in the selectivity of the reaction.[16] Thus,
the oxidation of the arene is proposed as the key step
of the mechanism (Fig. 3). To demonstrate that this
step is exergonic, the ΔG value for the oxidation of
pyrazole, which had the highest investigated oxidation
potential, was estimated to be -2.1 kcal. Therefore, the
catalytic cycle commences by protonation of SAS by
TFA to give the SAS-H+ cation, which is excited by
400 nm and transitions into the long-lived triplet state
resulting radical cation is subsequently attacked by a
bromide anion. Hydrogen abstraction by
a
hydroperoxyl radical yields the product and hydrogen
peroxide.[17] The formation of hydrogen peroxide
enables
a
second mechanistic pathway via
electrophilic bromination by hypobromous acid.[18]
However, control experiments indicated that this
process is much slower than the photocatalytic
pathway under the investigated conditions. The reason
for this is the slow reaction rate of the bromide anion
with H2O2.[19] Moreover, compounds 7 and 9 showed
neither addition of bromine to the triple bond nor α-
bromination of the ketone indicating that electrophilic
bromine species do not contribute significantly to the
conversion of the substrates. To clarify the role of
H2O2, a competition experiment between anisole and
trans-stilbene was performed, because in situ formed
HOBr or Br2 should react several orders of magnitude
faster with trans-stilbene than with anisole (Scheme 2).
However, no brominated stilbene was observed
5
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10.1002/adsc.201701276
Advanced Synthesis & Catalysis
One using a petrol ether and ethyl acetate (and/or methanol)
mixture as the mobile phase. For compounds containing a
free amine or a carboxylic acid functional group 1% v/v
triethylamine or trifluoroacetic acid were added to the ethyl
acetate. A 10 g column was employed with silica gel of type
60 M (40-63 µm, 230-440 mesh) by Merck as stationary
phase.
supporting the subordinate role of electrophilic
bromine species in the reaction mixture.
Acknowledgements
This work was supported by the German Science Foundation
(DFG) (GRK 1626, Chemical Photocatalysis). We thank Dr.
Rudolf Vasold (University of Regensburg) for his assistance in
GC-MS measurements and Regina Hoheisel (University of
Regensburg) for her assistance in cyclic voltammetry
measurements.
Scheme 2. Competition experiment between aromatic and
olefinic bromination to elucidate the role of H2O2 in the
reaction mixture.
References
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Conclusion
In summary, we have developed a new, photocatalytic
bromination method using protonated anthraquinone
as a strongly oxidizing photocatalyst. The procedure
extends previously reported methods and shows good
regio-selectivity and functional group tolerance
including double and triple bonds, ketones, amides and
amines, hydroxyl groups, carboxylic acids and
carbamates. The proton activation of anthraquinone
was shown using cyclovoltammetry. An interaction
between the aromatic substrates and SAS in the ground
as well as in the excited state was confirmed by UV-
VIS spectrometry and emission quenching
experiments. The readily available photocatalyst, very
simple reaction conditions and a good substrate scope
recommend the procedure for the mild oxidative
bromination of arenes and heteroarenes.
[9] L. Niu, H. Yi, S. Wang, T. Liu, J. Liu, A. Lei, Nat.
Commun. 2017, 10.1038/ncomms14226.
[10] W. Zhang, J. Gacs, I. W. C. E. Arends, F. Hollmann,
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[11] M. H. V. Huynh, T. J. Meyer, Chem. Rev. 2007, 107,
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Experimental Section
[12]S. A. Carlson, D. M. Hercules, J. Am. Chem. Soc. 1971,
93, 5611 − 5616.
[13] K. Ohkubo, A. Fujimoto, S. Fukuzumi, J. Am. Chem.
Soc. 2013, 135, 5368 − 5371.
General procedure for the bromination of arenes and
heteroarenes
[14] a) J. Najbar, M. Mac, J. Chem. Soc. Farad. Trans.
1991, 87, 1523 − 1529; b) M. Rae, F. Perez-Balderas,
C. Baleizao, A. Fedorov, J. A. S. Cavaleiro, A. C.
Tomé, M. N. Berberan-Santos, J. Phys. Chem. B 2006,
110, 12809 − 12814.
Sodium anthraquinone sulfonate (1.6 mg, 0.005 mmol),
NaBr (20.6 mg, 0.2 mmol) and the substrate (0.1 mmol)
were weight into a 5 mL crimp cap vial. A stirring bar and
1 mL of a mixture of MeCN and H2O 1:1 were added and
the vial was sealed with a crimp cap with septum under air
atmosphere. Trifluoroacetic acid (15.4 µL, 0.2 mmol) was
added via syringe through the septum and the vial was
shaken briefly. The vial was placed approximately 2 cm
above a 400 nm LED and stirred under irradiation for 4 h.
After completion of the reaction, the reaction mixture was
poured into a 50 mL round bottom flask and diluted with
DCM. Silica was added, the solvent was evaporated from
the suspension and the residue was used as dry load for
column chromatography on an Biotage® IsoleraTM Spektra
[15] Addition of more 1,3 DMB lead to phase separation of
the MeCN H2O mixture.
[16] Pre-orientation and spatial proximity of substrate and
catalyst, e.g. like in enzymes or other templated
reactions, is known to be a prerequisite for selectivity.
See also: a) J. Svoboda, B. König, Chem. Rev. 2006;
106; 5413 − 5430; b) S. Poplata, A. Tröster, Y. Q. Zou,
T. Bach, Chem. Rev. 2016; 116; 9748 − 9815.
6
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10.1002/adsc.201701276
Advanced Synthesis & Catalysis
[17] The presence of oxidants, potentially H2O2, in the
reaction mixture after the reaction was completed has
been confirmed by a commercially available KI-starch
test.
[18] a) A. Podgorsek, S. Stavber, M. Zupana, J. Iskraa,
Tetrahedron Lett. 2006, 47, 7245 − 7247; b) K. V. V.
K. Mohan, N. Narender, P. Srinivasu, S. J. Kulkarni,
K. V. Raghavan, Synth. Commun. 2004, 34, 2143 −
2152.
[19] A. Mohammad, H. A. Liebhafsky, J. Am. Chem. Soc.
1934, 56, 1680 − 1685.
7
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Advanced Synthesis & Catalysis
COMMUNICATION
Photocatalytic oxidative bromination of electron-
rich arenes and heteroarenes by anthraquinone
Adv. Synth. Catal. Year, Volume, Page – Page
Daniel Petzold and Burkhard König*
8
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