Metal-Free Electrocatalytic Aerobic Hydroxylation of Arylboronic Acids

Article abstract of DOI:10.1021/acs.orglett.7b02483

Hydroxylation of arylboronic acids to aryl alcohols was realized by a scalable electrocatalytic method. The present electrochemical hydroxylation employs low-cost methyl viologen as an organic cathodic electrocatalyst and involves O₂ as a green and sustainable reactant. The electrochemical kinetic studies shown here can be a powerful tool to gain rich mechanistic and kinetic information and thus an in-depth understanding of the electrocatalytic mechanism.

Full text of DOI:10.1021/acs.orglett.7b02483

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free Electrocatalytic Aerobic Hydroxylation of Arylboronic
Acids
Jian Luo, Bo Hu, Alyssa Sam, and T. Leo Liu*
The Department of Chemistry and Biochemistry, Utah State University, Logan, Utah 84322, United States
S
* Supporting Information
ABSTRACT: Hydroxylation of arylboronic acids to aryl alcohols was realized by a scalable
electrocatalytic method. The present electrochemical hydroxylation employs low-cost methyl
viologen as an organic cathodic electrocatalyst and involves O2 as a green and sustainable reactant.
The electrochemical kinetic studies shown here can be a powerful tool to gain rich mechanistic and
kinetic information and thus an in-depth understanding of the electrocatalytic mechanism.
lectrocatalysis constitutes a powerful, versatile, and
environmentally benign protocol that has been intensively
synthesis. Notably, MV2+ containing salts can be easily prepared
from commercially available chemicals at low cost ($1.0/kg for
MVCl2, $8.8/kg for MV(PF6)2, see the Supporting Information
(SI) for details). In the literature, there are very few examples of
using MV2+ as a catalyst for electrochemical synthesis.9 In
addition, we noticed that the one-electron-reduced MV•+ cation
radical is highly air sensitive. Further literature research revealed
that MV•+ can reduce O2 to the superoxide, O2•−, and then
goes back to its original MV2+ state.10 This chemistry inspired
us to apply O2•− as an activated O2 reactant in organic reactions
through electrocatalysis.11 O2•− is a highly active species that is
widely involved in organic transformations, such as the
oxidation of amines and alcohols.11,12
The phenolic hydroxyl is an important functional group that
is widely present in drug molecules and natural products. There
are traditional thermal reactions that have been developed to
convert arylboronic acids into aryl alcohols.13 However, among
these methods either strong oxidants were needed13e,g or
transition metals were used.13c,d Recent studies reported that
photolytically generated O2•− is highly reactive with arylboronic
acids to produce corresponding aromatic alcohols.13a,b
However, the photocatalysis entailed expensive photocatalysts
and is not feasible to scale up. Herein, we demonstrate
MV(PF6)2 as a highly efficient and inexpensive organic
cathodic electrocatalyst for scalable electrochemical aerobic
hydroxylation of arylboronic acids to aryl alcohols involving O2
in air as a green reactant. In contrast, many reported
electrocatalytic synthesis are triggered by an anodic electro-
catalyst.3a,4c,7 In addition, in the literature, the utilization of
electrochemical analysis for mechanistic understanding has
been largely overlooked by synthetic chemists. Electrochemical
mechanistic and kinetic studies were conducted to gain an in-
depth understanding on the reaction catalyzed by the
MV(PF6)2 electrocatalyst. In particular, an arylboronic acid−
O2 adduct, instead of O2, was detected as the actual substrate
E
applied in the field of energy conversion, such as hydrogen
evolution, water oxidation, and carbon dioxide reduction, in the
last decades.1 However, applications of electrocatalysis in
organic synthesis have been largely underdeveloped, although
early pioneering studies demonstrated the applicability of
electrochemical synthesis.2 Until recently, electrochemical or
electrocatalytic organic synthesis has been advocated as a
promising approach for scalable and sustainable chemical
transformations that can be applied in chemical industries for
the following reasons.3 First, dangerous and toxic redox
reagents are replaced by electric current and less toxic reaction
waste, and byproducts are generated in the electrochemical
process.3c,4 Second, the redox control of a reaction can be
facilely achieved by the voltage of electrodes, and then, better
selectivity could be obtained than under the thermal reaction
conditions.3a,b Third, a wide range of functional groups were
tolerant to mild electrochemical conditions.2a,3b,4c Finally, the
electrochemical approach can supply higher energy efficiency as
compared to thermal and photochemical processes.4a,5
In noncatalytic electrochemical reactions, a heterogeneous
electron transfer between the substrate and the electrode is the
key step to generate reactive intermediates, followed by a series
of homogeneous chemical transformations to produce final
products.3a,6 To accelerate the electron transfer while avoiding
the over-oxidation/over-reduction of the substrates, and to
mitigate the passivation of the electrode, electron-transfer
mediators were commonly applied as electrocatalysts in
electrosynthesis,3a,4c,7 including N-oxyl radicals,3b,4c,d,7a triar-
ylamines,7b triarylimidazoles,7c and ferrocene.7d
Our group has applied methyl viologen (MV2+) and its
derivatives for redox flow battery applications.8 The redox
active MV2+ cation undergoes a reversible single-electron
reduction at −0.45 V (vs NHE, in aqueous solution)
corresponding to the MV2+/•+ couple. Meanwhile, both redox
states were extremely thermally stable. Hence, MV2+ with its
reversible and fast electron transfer can be a good candidate as
an electron-transfer mediator for the electrocatalytic organic
Received: November 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02483
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
undergoing electrochemical reduction by MV•+, the actived
catalyst.
investigate the synthetic effectiveness of the electrocatalytic
aerobic hydroxylation of arylboronic acids. After systematic
optimization of reaction conditions (see Table S1), a 10 mL
solution of 0.1 M 4-formylphenylboronic acid and 0.3 M Et3N,
0.01 M MV(PF6)2 in DMF with 0.1 M Bu4N(PF6) as
supporting electrolyte was electrolyzed in an undivided cell at
−1.0 V (vs Cp2Fe+/0) in air using the chronocoulometry (CC)
method with porous carbon as an anode and cathode and Ag/
Ag+ electrode as a reference (see the picture in the SI). Et3N
acts as a hydrogen atom donor. After the starting material was
consumed, 4-hydroxybenzaldehyde was isolated as the main
product with 87% yield and 66% faradic efficiency (FE) (Table
1, entry 1). In addition, control experiments confirmed the
The electrochemical study was first conducted on the MV2+/
O2/phenylboronic acid (PhB(OH)2) system. As shown in
Figure 1, O2 displayed a reversible one-electron reduction peak
Table 1. Substrate Scope of the Electrocatalytic Aerobic
a
Hydroxylation of Arylboronic Acids
Figure 1. CV curves of (a) O2-saturated DMF, (b) 0.1 M PhB(OH)2
in O2-saturated DMF, (c) 2.5 mM MV(PF6)2 under N2, (d) 2.5 mM
MV(PF6)2 with 0.1 M PhB(OH)2 under N2, (e) 2.5 mM MV(PF6)2
under O2, and (f) 2.5 mM MV(PF6)2 with 0.1 M PhB(OH)2 under
O2. All tests were conducted in DMF solution with 0.1 M Bu4NPF6 as
supporting electrolyte. Working electrode: glassy carbon, counter
electrode: carbon rod, reference electrode: Ag/Ag+, scan rate: 100
mV/s. All potential was versus ferrocenium/ferrocene (Cp2Fe+/0).
with E1/2 [O20/•‑] = −1.32 V (vs Cp2Fe+/0) (Figure 1a) and
became irreversible in the presence of PhB(OH)2 (Figure 1b).
It is because the superoxide radical anion (O2•−) was trapped
by the PhB(OH)2, and then the return peak disappeared. MV2+
showed a reversible redox signal with E1/2 [MV2+/•+] = −0.94 V
under N2 atmosphere (Figure 1c), and it remains unchanged in
the presence of PhB(OH)2 (Figure 1d). Under an O2
atmosphere, the peak current intensity of the reduction process
(MV2+ → MV•+) was slightly increased and that of the
oxidation process (MV•+→ MV2+) was slightly decreased
(Figure 1e and Figure S2). We believe there is an electron-
a
b
c
1.0 mmol scale reaction. 5.0 g scale reaction. 50 g scale reaction.
d
FE stands for faradaic efficiency.
necessity of MV2+, Et3N, electrolysis, and an O2 atmosphere
(Table S2, entries 2−7). When 2.0 equiv of benzoquinone
(BQ) was added into the reaction mixture to quench radical
intermediates (Table S2, entry 8), no product was found. The
observation indicated a radical reaction mechanism for this
reaction, which is consistent with the photocatalytic approach-
es.13a,b
•−
transfer equilibrium: MV•+ + O2 ↔ MV2+ + O2 (eq 1), and
the electron-transfer equilibrium resides on the side of MV•+
because of the less negative E1/2 [MV2+/•+] compared to E1/2
[O20/•−]. However, in the presence of both PhB(OH)2 and O2,
The MV2+/O2/arylboronic acid electrocatalytic system was
further applied to a wide scope of substrates. As shown in Table
1, moderate to high yields (59−92%) were obtained with
satisfactory faradic efficiency (51−76%) for all the aryl alcohols
from the corresponding substrates. In the case of PhB(OH)2,
79% isolated yield and 71% faradic efficiency was obtained from
a 1.0 mmol scale reaction (entry 3). Both electron-withdrawing
groups (e.g., Br, aldehyde, ester, cyano, and amide, entries 1, 2,
and 4−8) and electron-donating groups (e.g., methyl, methoxy,
and ethoxy, entries 9 and 10) of the substrate were tolerant to
the electrocatalytic reaction. However, the yields and faradic
efficiencies for electron-donating aryl alcohols (entries 9 and
10) were slightly lower than those of electron-withdrawing aryl
alcohols (entries 1, 2, and 4−8). It may be because the
electron-donating aryl alcohols were further oxidized on the
an obvious electrocatalytic current was observed with E1/2
=
−0.92 V, and the return peak completely disappeared (Figure
1f). It was interpreted that the reduced O2 was trapped by the
PhB(OH)2, and then, the chemical equilibrium eq 1 was shifted
to the MV2+ side. Comparing the CV curves a−f, the reductive
0/•−
potential of O2
was reduced by 0.4 V in the presence of
MV2+. Meanwhile, in the presence of O2 and PhB(OH)2, the
peak current intensity of MV2+ reduction was increased about 5
times (Figure 1c,f), which indicates that MV2+ is an efficient
catalyst for the reduction of molecule O2.
On the basis of the above half-cell results, potentiostatic
electrolysis experiments in a full cell were conducted to
B
DOI: 10.1021/acs.orglett.7b02483
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Letter
anode due to their lower oxidation potential. For the π-
conjugated aryl alcohols, the isolated yields and faradic
efficiencies were also satisfactory (89% and 82% yield, 62%
and 60% faradic efficiency for entries 11 and 12, respectively).
Pinacol boronates were also active substrates for the electro-
catalytic arylboronic acid hydroxylation. As shown in entry 13,
62% isolated yield and 54% faradic efficiency was obtained by
using phenylboronic acid pinacol ester as the starting material.
With the advantages of the facile setup and high yield, the
electrocatalytic arylboronic acid hydroxylation can be applied to
large-scale reactions. For example, a 5.0 g (41.0 mmol) scale
reaction of PhB(OH)2 (Table 1, entry 3) was conducted under
the same conditions with a slightly lower isolated yield than
that of the 1.0 mmol scale reaction (66% yield and 62% faradic
efficiency), likely because of the oxidation of phenol during a
longer reaction time. When the potentiostatic electrolysis was
applied to a 50 g (0.33 mol) scale reaction of 4-
formylphenylboronic acid, a higher yield and faradic efficiency
than those of the 1.0 mmol scale reaction were obtained (90%
yield and 71% faradic efficiency).
PhB(OH)2 (Lewis acid) and O2 (Lewis base) (see Scheme 1).
The Lewis basic O2 is believed to add to the vacant p-orbital of
Scheme 1. Proposed Mechanism for the Electrocatalytic
Arylboronic Acid Hydroxylation
To gain in-depth understanding of the electrochemical
reaction process, a systematic kinetic study was conducted.
When the CV curves were recorded in an O2 saturated DMF
solution with 2.5 mM MV(PF6)2, the catalytic current kept
increasing with increasing PhB(OH)2 (Figure S5a). The same
tests were carried out in a DMF solution of 2.5 mM MV(PF6)2
and 0.1 M PhB(OH)2 with increasing O2 partial pressure
(Figure S5c) and in a 0.1 M PhB(OH)2 solution with the
addition of MV(PF6)2 under O2 (Figure S5e) or air (Figure
S6). In each case, the catalytic current increased as the
concentration of PhB(OH)2, O2, or MV(PF6)2 was increased.
the Lewis acidic boron. Under both air and O2 atmosphere, the
catalytic current also exhibited a linear relationship with the
concentration MV(PF6)2 (Figure S5f), indicating a single
catalyst based mechanism.
According to the information obtained from the above
electrochemical studies and control experiments, the reaction
mechanism of the electrocatalytic arylboronic acids hydrox-
ylation is proposed in Scheme 1. PhB(OH)2 first formed an
adduct with O2, and then the PhB(OH)2−O2 adduct was
reduced by MV•+, which comes from the electrochemical
reduction of MV2+ at −0.92 V (vs Cp2Fe+/0). This
homogeneous electron-transfer reaction would recover MV2+
icat/ip = (n/0.4463)(RTkobs/Fν)1/2
(1)
•−
and generate a PhB(OH)2-O2 radical anion. The subsequent
abstraction of a hydrogen atom and then 1,2-aryl shift
proceeded to give the final phenolic product. Et3N was
oxidized in the anodic process followed by a hydrogen atom
transfer step to generate an iminium cation. Our proposed
mechanism was further supported by the in situ 1H NMR study
(Figure S1). In the previous proposed photocatalytic
The turnover frequency (TOF, i.e., kobs) of the electro-
catalytic reaction under pseudo-first-order conditions can be
calculated using the ratio of icat/ip using eq (S1).14 Here, icat is
the catalytic current and ip is the peak current for the reduction
of MV2+, kobs is the first order rate constant, F is Faraday
constant, ν is the CV scan rate, R is the gas constant, and n
equals 1 for one electron process. The MV2+/O2/PhB(OH)2
system with 2.5 mM MV2+ and 0.1 M PhB(OH)2 exhibited
TOF of 16.1 s−1 under O2 (4.8 s−1 under air); however, in the
absence of MV2+ catalyst, the reductive current just slightly
increased (Figure 1a and 1b). With a PhB(OH)2 concentration
from 0 to 100 mM, a plot of the TOF versus PhB(OH)2
concentration is linear (Figure S5b), indicating that the
catalytic rate is first order in PhB(OH)2, giving a rate constant
as k = 1.8 × 102 s−1·M−1. Similarly, the first order of the
catalytic rate in O2 was indicated by the linear relation of TOF
versus O2 partial pressure (Figure S5d). The first order of the
catalytic rate in both PhB(OH)2 and O2 implied that the
arylboronic acids hydroxylation reaction was not carried out
through a stepwise oxygen-reduction/arylboronic acid−hydrox-
ylation mechanism as proposed previously.13a,b Instead, a
MV2+/O2/PhB(OH)2 three-component reaction was a key
mechanism,13a,b the reduction of O2 to O2 takes place first,
•−
•−
and then the resulting O2 will react with PhB(OH)2 to form
•−
PhB(OH)2−O2 radical anion. Thanks to the advantages of
molecular electrocatalysis, the new mechanism based on the
formation and reduction of the PhB(OH)2−O2 adduct was
discovered and elucidated the catalytic nature of aerobic
hydroxylation of arylboronic acids.
In summary, we report an electrochemical approach for
aerobic hydroxylation of arylboronic acids to aryl alcohols
catalyzed by methyl viologen (MV2+) that acts as an electron-
transfer mediator to reduce an arylboronic acid−O2 adduct to
•−
an arylboronic acid−O2 radical anion, a key elementary
reaction. The reduction potential of O2 was reduced by 0.4 V in
the presence of MV2+ and an arylboronic acid while the faster
rate of the reduction of O2 was achieved through MV2+
catalysis. The wide substrate scope, satisfactory yield and
faradic efficiency, and facile experimental setup as well as the
low cost catalyst makes the electrocatalysis a promising
approach for arylboronic acids hydroxylation. In light of the
1
elementary reaction. In a control experiment, the obvious H
NMR spectroscopic changes of PhB(OH)2 in CD3CN were
observed by bubbling with O2 (Figure S7). Specifically, a new
set of phenyl proton resonances were observed at δ = 7.79,
7.49, and 7.41 ppm in comparison to the original set of phenyl
proton resonances signal at δ = 8.28, 7.68, and 7.59 ppm. We
propose that there is a Lewis acid/base adduct formed between
•−
high activity and broad applications of O2 in organic
synthesis, the simple and benign MV2+/O2 electrocatalytic
system has great potential to be applied in other organic
transformations that are currently underway in our laboratory.
C
DOI: 10.1021/acs.orglett.7b02483
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Catal. 2015, 5, 5283. (c) Miyata, A.; Murakami, M.; Irie, R.; Katsuki,
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02483.
■
S
(13) (a) Luo, J.; Zhang, X.; Zhang, J. ACS Catal. 2015, 5, 2250.
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(c) Inamoto, K.; Nozawa, K.; Yonemoto, M.; Kondo, Y. Chem.
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Experimental details and additional figures (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: leoliu@usu.edu.
ORCID
T. Leo Liu: 0000-0002-3698-1096
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Utah State University for providing the faculty
startup funding to T.L.L. to support this work.
■
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DOI: 10.1021/acs.orglett.7b02483
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