Photocatalytic hydroxylation of arylboronic acids using continuous flow reactors

Article abstract of DOI:10.1039/c4ra15588b

The photocatalytic oxidation of mono- and di-substituted arylboronic acids to phenols has been investigated using a continuous flow photoreactor fitted with white LEDs. An EtOH-H₂O solvent system accelerated conversion at 2 MPa; whereas reactions at atmospheric pressure allowed for moderately efficient desymmetrisation.

Full text of DOI:10.1039/c4ra15588b

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Photocatalytic hydroxylation of arylboronic acids
using continuous flow reactors†
Cite this: RSC Adv., 2015, 5, 6501
Ines G. T. M. Penders,a Zacharias Amara,a Raphael Horvath,a Kai Rossen,b
`
a
ac
*
*
Martyn Poliakoff and Michael W. George
Received 23rd October 2014
Accepted 17th December 2014
DOI: 10.1039/c4ra15588b
www.rsc.org/advances
The photocatalytic oxidation of mono- and di-substituted arylboronic dyes such as methylene blue exhibited Â40 higher activity. Even
acids to phenols has been investigated using a continuous flow pho- so, the batch photosynthesis of phenols requires relatively long
toreactor fitted with white LEDs. An EtOH–H2O solvent system irradiation times (>6 h) using O2 saturated solutions.
accelerated conversion at 2 MPa; whereas reactions at atmospheric
Long reaction times are among the most signicant limita-
tions in the scale-up of current batch photochemical
processes.21,22 This is due to the fact that large volumes of
reaction mixtures impede efficient light penetration. The use of
molecular O2 also raises safety issues.23 Flow chemistry has
therefore recently emerged as a promising technology to avoid
major problems associated with photochemistry24 and oxygen-
ation reactions.25,26 It can operate with a larger surface to
volume ratio and enhanced mixing, which leads to more effi-
cient light irradiation and therefore, shorter reaction times are
typically observed. The use of O2 in ow is also safer than in
batch because reactions are conned to smaller volumes.27,28
The increased performances of ow over batch oxidations can
also permit the use of air instead of pure O2 which leads to
inherently safer high pressure processes.27
pressure allowed for moderately efficient desymmetrisation.
Phenols are ubiquitous in organic chemistry and form the
central units of many natural products, pharmaceuticals and
ne chemicals.1,2 However, common strategies for producing
phenols use either harsh conditions or metal-catalysed
hydroxylation.3 Since the 1930s, boronic acids have been
perceived as potential substrates for the development of alter-
native hydroxylation routes to phenols.3–6 Although direct
boronic acid hydroxylation has received attention, it oen
requires the use of strong oxidising agents or toxic metal cata-
lysts.3,7–14 Recently, a number of alternative methods have been
described, based on the generation of superoxide free radical
species (O2cÀ).15,16 In this context, photocatalysis has emerged
as a promising methodology17–19 which is compatible with a
variety of substrates and catalysts, including metal-free dyes.17
This procedure is attractive due to its broad applicability with
readily available catalysts and mild operating conditions; a
general reaction pathway is shown in Scheme 1. Visible light
absorption by the photocatalyst is followed by electron transfer
from the reductive quencher to the photocatalyst. The reduced
photocatalyst transfers an electron to molecular oxygen to
generate O2cÀ which reacts with the boronic acid. Aer hydro-
lysis, the reaction yields phenol with high selectivity.18 Scaiano
and co-workers17,20 recently outlined important mechanistic
details of the reaction and, in particular, found that organic
We have previously reported the continuous photo-oxidation
with singlet oxygen (1O2) by introducing the use of supercritical
CO2 as a solvent which is non-ammable and non-toxic.25,29–33
Here, we report a continuous ow strategy in aqueous mixtures
that allows rapid photocatalysed oxidations of arylboronic
acids. Our approach combines reactor and process design to
aSchool of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD,
UK. E-mail: mike.george@nottingham.ac.uk; martyn.poliakoff@nottingham.ac.uk
b
¨
Sano-Aventis Deutschland GmbH, Industriepark Hochst, 65926 Frankfurt, Germany
cDepartment of Chemical and Environmental Engineering, University of Nottingham
Ningbo China, 199 Talking East Road, Ningbo 315100, China
Scheme 1 General photoredox pathway for the hydroxylation of
arylboronic acid. PC refers to the photocatalyst and RQ stands for
reductive quencher.
† Electronic supplementary information (ESI) available: Experimental details and
1H NMR spectra. See DOI: 10.1039/c4ra15588b
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Table 1 Conversion of 1 to 2, in MeOH
offer higher levels of control and thus a more efficient proce-
dure. Finally, selective desymmetrisation of a di-substituted
arylboronic acid is investigated.
Flow rateb/
Reductive
quencher
Entry
mL minÀ1
Photocatalyst
Conversionc
The ow experiments were carried out in a high pressure
tubular sapphire photoreactor with an upow arrangement, see
Fig. 1. The organic feed contained the dissolved substrate,
photocatalyst and reductive quencher in a ask open to air.
Additional air was dosed into the system using a Rheodyne unit
and subsequently mixed with the organics in a micro-mixer
before entering the photoreactor. The reactor was lled with 6
mm diameter glass beads to promote mixing and to reduce the
optical pathlength to prevent inner lter effects. Three banks of
high-power white light emitting diodes (LEDs) provided visible
irradiation and the sapphire tube was surrounded by a
concentric transparent cooling jacket for temperature control
(see ESI†).
1
2
3
4a
5
6
7
8
9
0.1
0.4
0.1
0.1
0.1
0.4
0.8
0.1
0.8
[Ru(bpy)3]2+
[Ru(bpy)3]2+
[Ru(bpy)3]2+
[Ru(bpy)3]2+
RB
RB
RB
RB
RB
iPr2EtN
iPr2EtN
AA
>99%
27%
95%
43%
>99%
>99%
54%
42%
9%
AA
iPr2EtN
iPr2EtN
iPr2EtN
AA
AA
a
b
The reactor was not lled with glass beads. Air : 1 is 67 : 1.
c
Measured by 1H NMR.
We initially studied the reaction of phenylboric acid (1) to
phenol (2) (Scheme 2), employing an excess of the sacricial
electron donor N,N-diisopropylethylamine (iPr2EtN), as
described previously.17,18 Rose Bengal (RB) and [Ru(bpy)3]2+ were
used as photocatalysts providing an opportunity to compare
organic and transition-metal catalysts. We also investigated the
use of both iPr2EtN and ascorbic acid (AA) as reductive
quenchers for the photocatalytic cycle. As the reaction requires
a highly polar environment, DMF and CH3CN have been used
previously for similar reactions17,18 as well as protic solvents
such as MeOH, which resulted in similar reaction efficiency.
Table 1 summarises our results where 1 (0.05 M in MeOH), the
desired photocatalyst (2 mol%) and 2 equivalents of reductive
quencher were pumped into the photoreactor. The addition of
glass beads had a dramatic effect increasing the reactor effi-
ciency despite the fact that it considerably lowers the internal
volume and, hence, the residence time (entries 3 and 4). Rose
Bengal was found to be more efficient in the presence of amine
rather than ascorbic acid (entries 5 and 8). With [Ru(bpy)3]2+,
the efficiency with both reductive quenchers was high, however,
as with Rose Bengal, the amine gave superior conversion
(entries 1 and 3). In order to optimise the reaction, we tested the
efficiency of both photocatalysts with the amine as the reductive
quencher under similar conditions. At 0.4 mL minÀ1, Rose
Bengal gave almost quantitative conversion whereas lower effi-
ciency was obtained with [Ru(bpy)3]2+ (entries 2 and 6). When
the conditions from entry 6 in Table 1 were replicated in batch,
full conversion was observed only aer 5 hours, which suggests
that these ow experiments are already 15 times more produc-
tive than the batch synthesis.
Interestingly, when the solvent was changed from MeOH to
EtOH or EtOH–H2O (1 : 1) mixtures, the reaction showed
increased conversion at xed ow rates (see Table 2). We
investigated the effect of varying the dosing of air. At a
reasonably high ow rate the air to substrate ratio was found to
be at an optimum at ca. 67 : 1. According to previous studies,17
the use of pure oxygen is expected to increase kinetics. However,
increasing the air to substrate ratio led to lower conversion
which might be attributed to a decrease in residence time
(entry 4). Increasing the system pressure to 2 MPa resulted in
full conversion at 0.8 mL minÀ1 (entry 7). This increase in
pressure meant that the ow rate could be increased to 2.4 mL
minÀ1 while maintaining full conversion (entry 8) which gives a
productivity of ca. 3.4 g of phenol aer 5 h. In batch, the full
conversion of 1 to 2 took 5 h on a 0.125 g scale.34 A control
Fig. 1 The sapphire tubular photoreactor in upflow configuration. The
organic feed is pumped using a HPLC piston pump and air is dosed via
a dosing valve (Rheodyne). Both the liquids and gas are mixed in a static experiment without photocatalyst resulted in only traces of
micro-mixer M1 before entering the reactor which contains glass
phenol, demonstrating the need for a photocatalyst in this
beads. The upflow configuration was chosen to minimise the impact
process. This is consistent with the work of Jiang et al.,35 who
of air dosing on the residence time.
showed that prolonged UV irradiation is required to carry out
this reaction in the absence of a photocatalyst.
Aer having evaluated the reaction performances of our high
pressure continuous ow reactor, we were keen to test whether
such a system could also afford improvements in terms of
selectivity, by attempting a desymmetrisation reaction. To the
best of our knowledge, there have been no previous examples of
aryldiboronic acid desymmetrisations. Furthermore, there have
Scheme 2 Continuous flow aerobic hydroxylation of phenylboric acid
been very few precedents of desymmetrisation reactions carried
(1) to phenol (2).
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Table 2 Screening of reaction conditions using RB and iPr2EtN
Entry
Flow rate/mL minÀ1
Solvent
Air : 1 (O2 : 1)a
Pressure/MPa
Conv.b
1
2
3
4
5
6
7
8
9
0.8
0.8
0.8
0.8
0.8
0.8
0.8
2.4
2.8
3.2
MeOH
EtOH
67 : 1 (13 : 1)
67 : 1 (13 : 1)
67 : 1 (13 : 1)
134 : 1 (26 : 1)
33 : 1 (6 : 1)
0.1
0.1
0.1
0.1
0.1
0.1
2
2
2
2
54%
62%
67%
32%
13%
6%
>99%
>99%
80%
54%
EtOH–H2Od
EtOH–H2Od
EtOH–H2Od
EtOH–H2Od
EtOH–H2Od
EtOH–H2Od
EtOH–H2Od
EtOH–H2Od
c
—
67 : 1 (13 : 1)
67 : 1 (13 : 1)
67 : 1 (13 : 1)
67 : 1 (13 : 1)
10
a
1
Molar ratio. b Measured by H NMR. c No additional air. d Vol. 1 : 1.
out with continuous ow chemistry. Rare examples such as diol with greener alcoholic aqueous mixtures, the use of non-
mono-functionalisation,36,37 or thiophene dissymmetric lith- metallic inexpensive organic dyes and more environmentally
iation were reported.38 We therefore investigated the mono- friendly reductive quenchers such as ascorbic acid. The overall
hydroxylation of 1,4-benzenediboronic acid (3) (Scheme 3). benets of ow photochemistry demonstrated here show the
This symmetrical substrate has two boronic acid functionalities importance of such technologies for process development and
in para-positions where steric interactions are minimised and intensication. Finally, the underdeveloped option of using the
therefore cannot interfere with the second hydroxylation step. photocatalysed hydroxylation in desymmetrisation reactions
At the previously optimised conditions (Table 2, entry 8), the was assessed with a comparative study. Further work in this
reaction gave almost full conversion to hydroquinone (5) and no area is currently underway in our group.
selectivity to 4-hydroxyphenylboronic acid (4). Further experi-
ments at high pressure, using higher ow rates showed low
selectivity to 4. We speculated that this was related to the high
Acknowledgements
efficiency of the process. Indeed, improved selectivity to 4 was
achieved when the reaction was run at atmospheric pressure
and under stressed ow rate (0.4 mL minÀ1: 43% conversion
and 64% selectivity). These results were compared with batch
experiments where a higher selectivity was observed (see Tables
S1 and S2 in ESI†). Although the selectivity for the desired
product is modest, this serves as a proof of principle for a
substrate that does not bear any directing groups to facilitate
monofunctionalisation. Future optimisation could address the
selectivity and the residual starting material could in principle
be separated and recycled.
This work was supported by Sano and EPSRC Grant no. EP/
L021889/1. MWG thanks the Royal Society for a Wolfson Merit
Award. We thank Peter Fields, Richard Wilson and Mark Guyler
for technical assistance.
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