Electrophotocatalytic C?H Heterofunctionalization of Arenes

Article abstract of DOI:10.1002/anie.202100222

The electrophotocatalytic heterofunctionalization of arenes is described. Using 2,3-dichloro-5,6-dicyanoquinone (DDQ) under a mild electrochemical potential with visible-light irradiation, arenes undergo oxidant-free hydroxylation, alkoxylation, and amination with high chemoselectivity. In addition to batch reactions, an electrophotocatalytic recirculating flow process is demonstrated, enabling the conversion of benzene to phenol on a gram scale.

Full text of DOI:10.1002/anie.202100222

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11163–11167
International Edition: doi.org/10.1002/anie.202100222
German Edition: doi.org/10.1002/ange.202100222
Electrochemistry
À
Electrophotocatalytic C H Heterofunctionalization of Arenes
He Huang and Tristan H. Lambert*
Abstract: The electrophotocatalytic heterofunctionalization of
arenes is described. Using 2,3-dichloro-5,6-dicyanoquinone
(DDQ) under a mild electrochemical potential with visible-
light irradiation, arenes undergo oxidant-free hydroxylation,
alkoxylation, and amination with high chemoselectivity. In
addition to batch reactions, an electrophotocatalytic recirculat-
ing flow process is demonstrated, enabling the conversion of
benzene to phenol on a gram scale.
ideal. We hypothesized that adaptation to an electrophoto-
catalytic strategy might address some of the issues noted
above and thus enable a range of useful arene C-H
functionalizations.
We recently demonstrated the use of DDQ as an electro-
photocatalyst[9–11] for SNAr reactions with non-traditional
D
irect C-H functionalization provides a time-, effort-, and
resource-economical approach to synthesize substituted
arenes from simple precursors.[1] While transition metal
catalyzed strategies have arguably been the most well-studied
approach to accomplish such transformations,[2,3] reactions
initiated by single-electron oxidation of the arene have also
been explored. The oxygenation of arenes by direct electrol-
ysis has long been known (e.g. Figure 1A), although these
approaches tend to suffer from low yield, selectivity, and
scope.[4] More recently, visible-light photocatalysis has ena-
bled a number of powerful methods for arene functionaliza-
tion that do not require the use of metals or metal-directing
groups.[5] Because these photoredox reactions are typically
initiated by single-electron oxidation of the arene ring, they
tend to be performed with relatively electron-rich substrates
due to their lower oxidation potentials. In contrast, it has
proven more challenging to achieve such reactions with
weakly electron-deficient or electron-neutral arenes, for
example those bearing halogen atoms or benzene (1) itself,
because of their relatively high oxidation potentials. A
notable exception was reported by Fukuzumi, who described
the visible-light-induced hydroxylation of benzene (1) using
DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)
(4),
which has a sufficiently high excited state redox potential to
achieve the single-electron oxidation of benzene (Fig-
ure 1B).[6,7] Despite the groundbreaking nature of this
discovery, this process was limited to the small-scale hydrox-
ylation of benzene with a relatively high catalyst loading (30–
100 mol%). Subsequently, Kçnig showed that DDQ photo-
catalysis could achieve the direct amination of arenes using
nucleophiles such as carbamates and ureas, greatly expanding
the utility of this chemistry (Figure 1C).[8] However, the
relatively high catalyst loading and the use of tert-butyl nitrite
and air, which forms a potentially explosive mixture, were not
[*] Dr. H. Huang, Prof. Dr. T. H. Lambert
Department of Chemistry and Chemical Biology
Cornell University
122 Baker Laboratory, Ithaca, NY 14853 (USA)
E-mail: tristan.lambert@cornell.edu
Figure 1. A) Example of oxygenation of benzene by direct electrolysis.
B) DDQ photocatalyzed hydroxylation of benzene. C) DDQ photocata-
lyzed amination of benzene. D) Electrophotocatalytic arene heterofunc-
tionalization. E) Mechanistic rationale.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100222.
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substrates under mild conditions.[10b] Given that success, and
the Fukuzumi and Kçnig precedents, we speculated that this
electrophotocatalytic approach might be adapted to realize
an efficient arene heterofunctionalization strategy (Fig-
ure 1D). We anticipated that the process would operate by
a mechanism akin to the previous reports, wherein photo-
excited DDQ effects single electron transfer (SET) oxidiza-
tion of an arene 1 to furnish a radical cation 7 that can
undergo nucleophilic capture. The key difference is that DDQ
(4) would be regenerated by anodic oxidation of the reduced
DDQH2 (6), with concomitant cathodic reduction of protons
to form hydrogen gas completing the electrochemical reac-
tion. Thus, this electrophotocatalytic setup obviates the need
for a traditional oxidant like TBN. In this Communication, we
demonstrate the electrophotocatalytic heterofunctionaliza-
tion of arenes, including hydroxylation, alkoxylation, and
amination reactions, both in batch and in a recirculating flow
process.
We first examined the electrophotocatalytic coupling of
benzene (1) and water to form phenol (11) (Table 1). Our
initial condition choice was based on our previous study[10b]
and entailed subjecting benzene, 20 equivalents of water, and
10 mol% DDQ (4) to a 1.5 V controlled potential in an
undivided cell (carbon cathode, Pt anode) under visible light
irradiation (blue LED strip) in the presence of TBABF4 and
acetic acid. Under these conditions, phenol (11) was gener-
ated in 43% yield (entry 1). Changing the electrolyte to
LiClO4 resulted in an appreciably higher yield (55%, entry 2),
while lower catalyst loading resulted in diminished yield
(36% yield, entry 3). The catalyst, potential, and light were
necessary for this reaction (entries 4–6) which confirmed the
process was actually electrophotocatalytic. The product yield
was significantly diminished without the addition of acetic
acid (entry 7). With further screening, we found that a higher
yield (80%) could be realized by using more equivalents of
water (50 equiv) and a longer reaction time of 48 h (entry 8).
Importantly, when we attempted the same reaction by direct
electrolysis without catalyst and light using up to 3.0 V
constant voltage, no phenol was observed (entry 9). Using the
optimized conditions but longer reaction time (96 h), the
reaction could be scaled up (entry 10).
Using the optimized conditions, the generality of the
hydroxylation reaction was explored (Table 2). Bromoarene
products 12 and 13 were obtained in 55% and 50% yields
with 10:1 to 4:1 regioselectivity, respectively (entries 1 and 2).
Meanwhile, both 1,3- and 1,2-dichlorobenzene underwent
hydroxylation with complete regioselectivity (entries 3 and
4). Benzophenone and 3-methylacetophenone also reacted,
furnishing phenol 16 in 46% yield and 17 in 52% yield,
respectively (entries 5 and 6). Despite the fact that these
electron-deficient arenes were reactive to the hydroxylation
procedure, substrates with two electronically differentiated
arenes were exclusively functionalized on the more electron-
rich ring (entries 7–10). Although these are obviously strongly
oxidizing conditions, potentially sensitive functionality in the
form of Boc-protected peptides (entries 11 and 12) or free
hydroxyl groups (entry 13) were tolerated, allowing for the
production of phenols 22–24.
Table 2: Electrophotocatalytic hydroxylation of arenes with water.
Table 1: Optimization studies
Entry Time [h] Electrolyte (equiv) Other
Yield [%][a,b]
1
2
3
4
5
6
7
8
9
10
28
28
28
28
28
28
28
48
48
96
TBABF4 (1)
LiClO4 (6)
LiClO4 (6)
LiClO4 (6)
LiClO4 (6)
LiClO4 (6)
LiClO4 (6)
LiClO4 (6)
LiClO4 (6)
LiClO4 (6)
–
–
43
55
36
0
0
<5
8
80
5% DDQ
no catalyst
no light
no electrolysis
no acid
50 equiv H2O
direct electrolysis[a]
4 mmol scale
0
66 (52)[c]
[a] See Supporting Information for detailed procedures. [b] Isolated
yields.
[a] See Supporting Information for detailed procedures. [b] Yields were
determined by UPLC. [c] Isolated yields.
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Table 3: Electrophotocatalytic heterofunctionalization of arenes.[a,b]
To further demonstrate the selectivity of this protocol, we
subjected a mixture of anisole (25), benzene (1), and
trifluorotoluene (26) to the electrophotocatalytic hydroxyl-
ation procedure [Eq. (1)]. In this case, phenol (11) was
generated exclusively while the other two arenes were left
untouched by these conditions. Intermediate 4* is insuffi-
ciently oxidizing to remove an electron from arenes with very
high oxidation potentials, while alkoxybenzenes or phenols
also do not undergo reaction, likely due to a rapid back-
electron transfer process that outcompetes nucleophilic
attack to the transient radical cation intermediate.[6]
In addition to the use of water to generate phenols, we
found that other nucleophiles could also be utilized (Table 3).
For example, the reaction of benzene with various alcohols
led to the formation of aryl ether products 25, 27–30
(entries 1–5). Methoxylation to generate 31 was readily
achieved (entry 6), and the deuterated analogue 32 could
also be accessed (entry 7). Alternatively, benzoic acid
(entry 8) or N-Boc alanine (entry 9) furnished aryl esters 33
and 34. In terms of nitrogen nucleophiles, benzamide
(entry 10), ethyl carbamate (entry 11), urea (entry 12), and
acetamide (entry 13) reacted with benzene in varying yields.
Amines were not productive (e.g. entry 14), likely due to the
acidic conditions. On the other hand, diphenylsulfonimide
readily participated (entry 15). Using ethylcarbamate, a vari-
ety of halogenated arenes could be derivatized (entries 16–
19). Meanwhile, tert-butylcarbamate was also productive to
furnish adduct 46 in 62% yield (entry 20).
To enable further scale up of this process, we adapted this
method to a continuous flow system.[12] Although continuous
flow has proven to be highly advantageous for photoredox
catalysis, it has only just recently been adapted for electro-
photocatalysis.[9j,k,m] Because in the current reactions the
photochemical portion of the process is much slower than the
electrochemical one, we were able to couple a small electro-
chemical cell with one or more photochemical chambers using
an inexpensive peristaltic pump. Using the hydroxylation of
benzene as a representative reaction, we employed a flow set-
up (Figure 2) with a residence time of 3 min and a 1.5 V
controlled potential undivided cell, with which phenol (11)
was formed in 65% yield on a 0.4 mmol scale in 18 h
(Figure 2B). For a larger scale (4 mmol), a longer reaction
time was needed; however, by equipping two photoreactor
channels the reaction time could be reduced with minimal
impact on yield (Figure 2C). Equipping three flow channels
further decreased the reaction time to 22 h and improved the
yield (Figure 2D). Notably, using the three channel set-up,
a 15 mmol scale reaction delivered a 56% yield of phenol (11)
in 60 h.
[a] See Supporting Information for detailed procedures. [b] Isolated
yields. [c] Yields were determined by UPLC. [d] Without AcOH.
In conclusion, we have developed an electrophotocata-
lytic procedure for the C-H hydroxylation, alkoxylation,
and amination of arenes with high chemoselectivity.[13]
Using DDQ as an electrophotocatalyst, water, alcohols,
acids, amides or carbamates can be appended to arenes
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[5] For selected reviews: a) S. Fukuzumi, K. Ohkubo, Org. Biomol.
Chem. 2014, 12, 6059 – 6071; b) N. A. Romero, D. A. Nicewicz,
Chem. Rev. 2016, 116, 10075 – 10166; c) S. Crespi, M. Fagnoni,
Chem. Rev. 2020, 120, 9790 – 9833; For selected examples:
d) D. P. Hari, P. Schroll, B. Kçnig, J. Am. Chem. Soc. 2012, 134,
2958 – 2961; e) J. W. Beatty, J. J. Douglas, K. P. Cole, C. R. J.
Stephenson, Nat. Commun. 2015, 6, 7919 – 7925; f) N. A.
Romero, K. A. Margrey, N. E. Tay, D. A. Nicewicz, Science
2015, 349, 1326 – 1330; g) K. A. Margrey, J. B. McManus, S.
Bonazzi, F. Zecri, D. A. Nicewicz, J. Am. Chem. Soc. 2017, 139,
11288 – 11299.
[6] a) K. Ohkubo, A. Fujimoto, S. Fukuzumi, J. Am. Chem. Soc.
2013, 135, 5368 – 5371; b) K. Ohkubo, K. Hirose, S. Fukuzumi,
Chem. Eur. J. 2015, 21, 2855 – 2861.
[7] A related photocatalytic arene hydroxylation/ amination reac-
tion that requires UV light has also been reported. Y.-W. Zheng,
B. Chen, P. Ye, K. Feng, W. Wang, Q.-Y. Meng, L.-Z. Wu, C.-H.
Tung, J. Am. Chem. Soc. 2016, 138, 10080 – 10083.
[8] a) S. Das, P. Natarajan, B. Kçnig, Chem. Eur. J. 2017, 23, 18161 –
18165; For a recent review, see: b) P. Natarajan, B. Kçnig, Eur. J.
Org. Chem. 2021, https://doi.org/10.1002/ejoc.202100011.
[9] For examples of electrophotocatalysis or photoelectrocatalysis,
see: a) J.-C. Moutet, G. Reverdy, J. Chem. Soc. Chem. Commun.
1982, 654 – 655; b) R. Scheffold, R. Orlinski, J. Am. Chem. Soc.
1983, 105, 7200 – 7202; c) H. Tateno, S. Iguchi, Y. Miseki, K.
Sayama, Angew. Chem. Int. Ed. 2018, 57, 11238 – 11241; Angew.
Chem. 2018, 130, 11408 – 11411; d) H. Yan, Z.-W. Hou, H.-C. Xu,
Angew. Chem. Int. Ed. 2019, 58, 4592 – 4595; Angew. Chem.
2019, 131, 4640 – 4643; e) F. Wang, S. S. Stahl, Angew. Chem. Int.
Ed. 2019, 58, 6385 – 6390; Angew. Chem. 2019, 131, 6451 – 6456;
f) L. Zhang, L. Liardet, J. Luo, D. Ren, M. Grꢀtzel, X. Hu, Nat.
Catal. 2019, 2, 366 – 373; g) W. Zhang, K. Carpenter, S. Lin,
Angew. Chem. Int. Ed. 2020, 59, 409 – 417; Angew. Chem. 2020,
132, 417 – 425; h) N. G. W. Cowper, C. P. Chernowsky, O. P.
Williams, Z. K. Wickens, J. Am. Chem. Soc. 2020, 142, 2093 –
2099; i) X. Lai, X. Shu, J. Song, H.-C. Xu, Angew. Chem. Int. Ed.
2020, 59, 10626 – 10632; Angew. Chem. 2020, 132, 10713 – 10719;
j) Y. Qiu, A. Scheremetjew, L. H. Finger, L. Ackermann, Chem.
Eur. J. 2020, 26, 3241 – 3246; k) P. Xu, P. Chen, H.-C. Xu, Angew.
Chem. Int. Ed. 2020, 59, 14275 – 14280; Angew. Chem. 2020, 132,
14381 – 14386; l) L. Niu, C. Jiang, Y. Liang, D. Liu, F. Bu, R. Shi,
H. Chen, A. D. Chowdhury, A. Lei, J. Am. Chem. Soc. 2020, 142,
17693 – 17702; m) H. Yan, J. Song, S. Zhu, H.-C. Xu, CCS Chem.
Figure 2. A) Electrophotocatalytic hydroxylation of benzene in flow
using B) one, C) two, or D) three photoreactor channels.
without the use of external oxidants. This work thus adds
a new set of tools to the arsenal of direct C-H functionaliza-
tion protocols.
Acknowledgements
Financial support for this work was provided by NIGMS (R35
GM127135).
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkoxylation · amination · electrophotocatalysis ·
hydroxylation · photochemistry
ˇ
2021, 3, 317 – 325; n) S. Wu, J. Zurauskas, M. Domanski, P. S.
Hitzfield, V. Butera, D. J. Scott, J. Rehbein, A. Kumar, E.
Thyrhaug, J. Hauer, J. P. Barham, Org. Chem. Front. 2021, 8,
1132 – 1142.
[1] a) J.-Q. Yu, Z. Shi, C-H Activation, Springer, Berlin, Heidelberg,
2010; b) H. M. L. Davies, D. Morton, J. Org. Chem. 2016, 81,
343 – 350.
[10] For examples of electrophotocatalysis from our group, see: a) H.
Huang, Z. M. Strater, M. Rauch, J. Shee, T. J. Sisto, C. Nuckolls,
T. H. Lambert, Angew. Chem. Int. Ed. 2019, 58, 13318 – 13322;
Angew. Chem. 2019, 131, 13452 – 13456; b) H. Huang, T. H.
Lambert, Angew. Chem. Int. Ed. 2020, 59, 658 – 662; Angew.
Chem. 2020, 132, 668 – 672; c) H. Huang, Z. M. Strater, T. H.
Lambert, J. Am. Chem. Soc. 2020, 142, 1698 – 1703; d) H. Kim,
H. Kim, T. H. Lambert, S. Lin, J. Am. Chem. Soc. 2020, 142,
2087 – 2092; e) T. Shen, T. H. Lambert, Science 2021, 371, 620 –
626.
[11] For selected reviews and highlights, see: a) L. Capaldo, L. L.
Quadri, D. Ravelli, Angew. Chem. Int. Ed. 2019, 58, 17508 –
17510; Angew. Chem. 2019, 131, 17670 – 17672; b) J. P. Barham,
B. Kçnig, Angew. Chem. Int. Ed. 2020, 59, 11732 – 11747; Angew.
Chem. 2020, 132, 11828 – 11844; c) J. Liu, L. Lu, D. Wood, S. Lin,
ACS Cent. Sci. 2020, 6, 1317 – 1340; d) Y. Yu, P. Guo, J.-S. Zhong,
Y. Yuan, K.-Y. Ye, Org. Chem. Front. 2020, 7, 131 – 135; e) T. H.
Meyer, I. Choi, C. Tian, L. Ackermann, Chem 2020, 6, 2484 –
2496.
[2] a) J. Hartwig, Organotransition Metal Chemistry: From Bonding
to Catalysis, University Science Books, Sausalito, CA, 2010; For
selected recent reviews: b) P. Gandeepan, L. Ackermann, Chem
2018, 4, 199 – 222; c) S. Rej, Y. Ano, N. Chatani, Chem. Rev. 2020,
120, 1788 – 1887.
[3] Examples of direct arene heterofunctionalization: a) S.-i. Niwa,
M. Eswaramoorthy, J. Nair, A. Raj, N. Itoh, H. Shoji, T. Namba,
F. Mizukami, Science 2002, 295, 105 – 107; b) Y. Morimoto, S.
Bunno, N. Fujieda, H. Sugimoto, S. Itoh, J. Am. Chem. Soc. 2015,
137, 5867 – 5870; c) J. W. Han, J. Jung, Y.-M. Lee, W. Nam, S.
Fukuzumi, Chem. Sci. 2017, 8, 7119 – 7125; d) For a review on
catalytic phenol production: R. J. Schmidt, Appl. Catal. A 2005,
280, 89 – 103.
[4] For selected examples of electrochemical arene heterofunction-
alization: a) T. Tajima, Y. Kishi, A. Nakajima, Electrochim. Acta
2009, 54, 5959 – 5963; b) L. Eberson, E. Oberrauch, Acta Chem.
Scand. B 1981, 35, 193 – 196; c) Y.-H. So, J. Y. Becker, L. L.
Miller, J. Chem. Soc. Chem. Commun. 1975, 262 – 263; d) L.
Eberson, K. Nyberg, J. Am. Chem. Soc. 1966, 88, 1686 – 1691.
11166 www.angewandte.org
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[12] a) D. Cambiꢁ, C. Bottecchia, N. J. W. Straathof, V. Hessel, T.
Noꢂl, Chem. Rev. 2016, 116, 10276 – 10341; b) M. Elsherbini, T.
Wirth, Acc. Chem. Res. 2019, 52, 3287 – 3296.
[13] During the review of this manuscript, a preprint describing
a closely related method appeared: Z.-W. Hou, H. Yan, J. Song,
H.-C. Xu, 2021, DOI 10.26434/chemrxiv.13718392.v1.
Manuscript received: January 6, 2021
Revised manuscript received: February 10, 2021
Accepted manuscript online: March 4, 2021
Version of record online: April 12, 2021
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