Material-Efficient Microfluidic Platform for Exploratory Studies of Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201705148

We present an automated microfluidic platform for in-flow studies of visible-light photoredox catalysis in liquid or gas–liquid reactions at the 15 μL scale. An oscillatory flow strategy enables a flexible residence time while preserving the mixing and heat transfer advantages of flow systems. The adjustable photon flux made possible with the platform is characterized using actinometry. Case studies of oxidative hydroxylation of phenylboronic acids and dimerization of thiophenol demonstrate the capabilities and advantages of the system. Reaction conditions identified through droplet screening translate directly to continuous synthesis with minor platform modifications.

Full text of DOI:10.1002/anie.201705148

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Accepted Article
Title: Material-Efficient Microfluidic Platform for Exploratory Studies of
Visible-Light Photoredox Catalysis
Authors: Connor W Coley, Milad Abolhasani, Hongkun Lin, and Klavs
F. Jensen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705148
Angew. Chem. 10.1002/ange.201705148
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Angewandte Chemie International Edition
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Material-Efficient Microfluidic Platform for Exploratory Studies of
Visible-Light Photoredox Catalysis
[
a]
[a, b]
[a]
[a]
Connor W. Coley , Milad Abolhasani , Hongkun Lin , and Klavs F. Jensen*
Abstract: We present an automated microfluidic platform for in-flow studies of visible-light photoredox catalysis in liquid or gas-liquid reactions
at the 15 μL scale. An oscillatory flow strategy enables flexible residence time while preserving the mixing and heat transfer advantages of flow
systems. The adjustable photon flux possible with the platform is characterized using actinometry. Case studies of oxidative hydroxylation of
phenylboronic acids and dimerization of thiophenol demonstrate the capabilities and advantages of the system. Reaction conditions identified
through droplet screening translate directly to continuous synthesis with minor platform modifications.
Photoredox catalysis has rapidly grown as an attractive tool in
organic synthesis. Reactions which might otherwise require harsh
conditions (e.g., high temperatures, highly-reactive reagents) are
successfully performed under ambient conditions using visible
light to initiate photocatalyst-mediated electron transfer.[1] The
relatively high absorption of organometallic complexes within the
visible spectrum provides greater opportunity for selective
photochemical transformations compared to direct use of light
itself (i.e., UV irradiation).[1d, 2] The redox process, owing to the
long-lived photoexcited state of the activated photocatalyst,
enables a safer, cleaner, and more environmentally-friendly
approach to organic synthesis.[
characterization, optimization, and development of photocatalytic
reactions.[
4f]
In this study, building off our previous work with single-droplet
oscillatory flow reactors,[5] we report an automated platform
designed for screening and optimization of photocatalyzed liquid
or gas-liquid reactions (Figure 1c). Microreaction vessels (i.e.,
droplets) of 15 µL are prepared on-demand by a computer-
controlled liquid handler, injected into the system flowpath, and
moved within gas-filled fluoropolymer tubing to a horseshoe-
shaped photoreactor zone; the optically transparent reactor is
illuminated from the top using a high intensity LED integrated via
a custom-designed aluminum chuck. The reactor housing is
mounted on a thermoelectric plate for active temperature control.
Constant oscillatory motion of the droplet within the photoreactor
promotes gas/liquid mass transfer and ensures that the reaction
mixture remains well-mixed over the course of the reaction. After
the desired reaction time, a sample of the crude product mixture
(1-6 µL) is automatically injected into an LC/MS unit for analysis.
The modular platform offers some distinct advantages over
traditional continuous flow techniques. Oscillatory motion within
the reactor enables a wide range of residence times and
decouples reaction time and mass transfer rates (i.e., via linear
velocity). The carrier gas phase is easily reconfigurable between
reactive gases (e.g., oxygen) and inert gases (e.g., argon)
depending on the particular chemistry being studied. In addition,
1c]
In a typical experimental set-up for a photochemical reaction,
a high-powered light source is placed next to the reaction vessel
(Figure 1a). The vessel headspace may be pressurized to
increase the gas solubility and accelerate the gas-liquid reaction.
Despite the prevalence of batch processes, they are often time-
and labor-intensive to set up and do not provide precise control
over reaction conditions. For example, strong visible-light
irradiation can heat reaction mixtures, leading to an unknown
increase in the reaction temperature, thereby making it
challenging to decouple the effects of heat and photocatalyst
activation. Moreover, the exponential decay of light intensity with
penetration depth results in only partial activation of the available
photocatalyst within the reaction vessel at each moment in time,
necessitating reaction timescales on the order of hours to days.
Flow chemistry has addressed the aforementioned limitations
of batch photochemical reactors by reducing the characteristic
reaction vessel length scale from centimeters to hundreds of
micrometers.[ Small-scale continuous flow reactors (Figure 1b)
typically use small inner diameter transparent tubing (ca. 1/16 or
G
the carrier gas pressure, P , can be adjusted (0 - 2 MPa) to study
its effect on reaction kinetics. Furthermore, the system can be
reconfigured from discrete screening (oscillatory flow) to
production (continuous flow) under identical reaction conditions.
To better understand the irradiation characteristics of the
oscillatory flow platform, actinometry was used to quantify the
photon flux in the reactor. The absorbed photon flux (photons per
unit time) can be calculated from the rate of reaction (molecules
consumed per unit time) normalized by the reaction’s known
quantum yield. Here, we use the aerobic oxidation of 9,10-
diphenylanthracene (1, DPA) to the peroxide 2 in the presence of
3]
1/32 in.) coiled around a light source. The small length scale
significantly enhances the absorbed photon flux and gas-liquid
mass transfer.[ Nevertheless, the milliliter-scale reagent volumes
required per reaction condition make it challenging to apply
continuous flow chemistry approaches to the screening,
4]
3 2
Ru(bpy) Cl
, shown in Scheme 1a. [6]
Figure 2 shows the results of the actinometry experiments.
Using a fiber-coupled broad spectrum light source and UV-Vis
spectrometer at the optical detection point (Figure 2a), the
absorbance spectrum of the reaction mixture is obtained in real-
time (Figure 2b). Monitoring DPA absorbance at 372 nm under
different irradiation intensities as measured by LED input power
[
[
a]
b]
C. W. Coley, Dr. M. Abolhasani, Dr. H. Lin, Prof. K. F. Jensen
Department of Chemical Engineering
Massachusetts Institute of Technology
77 Massachsuetts Avenue, Cambridge, MA 02139
E-mail: kfjensen@mit.edu
Department of Chemical and Biomolecular Engineering
North Carolina State University
(Figure 2c) in combination with fitted first-order rate coefficients
allow the calculation of absorbed photon flux. For example, at 400
911 Partners Way, Raleigh, NC 27695
-
10
-2
mW, the absorbed photon flux is ~ 3x10 mol hν/s, or 2x10 mol
hν/m /s (Figure 2d).
Supporting information for this article is given via a link at the end of
the document.
3
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COMMUNICATION
Figure 1. Schematics of traditional (a) batch and (b) continuous flow strategies for photochemical synthesis. (c) The experimental setup developed for single droplet
studies of visible-light photoredox catalysis using an oscillatory flow strategy.
To demonstrate the versatility and efficacy of the developed
flow chemistry platform for in-flow studies of visible-light
photocatalyzed reactions, we first consider the oxidative
hydroxylation of arylboronic acids to their corresponding phenols.
Phenols are prevalent in biologically active compounds and small-
molecule drugs, but their late-stage synthesis through traditional
nucleophilic substitution can be challenging due to functional
group incompatibilities and generation of side products.[7] Among
a
Ph
Ph
LED
23 °C
460 nm),
(
3Cl2 6H O
-
Ru(bpy)
2
O
O
ACN, 101 kPa air
Ph
Ph
1
2
b
the many approaches to this transformation, Zou et al.[ have
reported the use of Ru(bpy) Cl as a photocatalyst to generate
in situ, which readily reacts at the boron
8]
LED (460 nm), 23 °C
3Cl2 - 6H O mol%)
OH
B
Ru(bpy)
2
(2
3
2
R
R
S
OH
•-
radical oxygen anion O
2
OH Et N equiv.), DMF, 791 kPa O /air
(2
3
2
center (Figure 3a). Despite achieving high yields (71-96%), the
use of batch vessels and need for long reaction times (16-72
hours) are obstacles to translating this approach to the production
scale. We thus apply our flow chemistry platform to study this
reaction, for the first time, under conditions one might employ for
continuous flow synthesis to convert various phenylboronic acids
3
4
c
LED
T
(460 nm),
SH
Eosin Y mol%)
(
1
S
TMEDA
ACN, 481 kPa air
1 equiv.),
(
5
6
(3) to the corresponding phenols (4), shown in Scheme 1b.
An initial screening of LED photon fluxes at fixed residence
times of 3.6 and 25 minutes for phenylboronic acid is shown in
Figure 3b. At low residence times, higher light intensity is always
preferred; however, at longer residence times, an internal
optimum at 6 W is observed. Figure 3c corroborates this trade-off
via the time evolution of phenol yield at the optimum (6 W) and
maximum (37 W) LED input powers. The apparent zeroth order
kinetics with respect to 3 at 6 W demonstrates that the
photocatalytic cycle is initially rate-limiting at this low input power
Scheme 1. Representative visible-light photocatalyzed reactions. (a) Oxidation
of 9,10-diphenylathracene as chemical actinometer; (b) oxidative
hydroxylation of phenylboronic acids; (c) dimerization of thiophenol to
diphenyldisulfide.
a
(Figure 3c inset).
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Figure 2. (a) Modified oscillatory photochemical reactor for in-situ actinometry
measurements; (b) time evolution of the UV absorption spectra of the reaction
mixture during oxidation of 1; (c) decay in the absorbance of 1 at 372 nm under
different irradiation conditions; (d) calculated absorbed photon flux at different
LED powers.
Figure 3. (a) Mechanism of the photocatalyzed oxidative hydroxylation of
[
8]
arylboronic acids, reproduced from ; (b) screening of LED currents at fixed
residence times of 3.6 minutes (blue) and 25 minutes (red) for the oxidation of
3 (R=H); (c) time evolution of phenol yield under two LED powers.
To better understand this phenomenon, additional
substrates (3, R = Me, Et, MeO, F, CN, Cl) were studied under
similar conditions. The maximum yields observed for each
substrate are summarized in Table S1. Time studies of the
selected substrates at 6 W and 37 W are shown in Figure 4ab and
bridges are essential to realize protein folding[11] and synthesize
protein analogues.[12] As shown in Figure 5bc, high conversions
of 5 to 6 was achieved in short reaction times, even at very low
LED powers of 38 and 64 mW. At higher powers of 2.8 and 37 W,
conversion is completed within 2 minutes at 23 °C and within 1
minute at 35 °C. The enhanced reaction rate is directly associated
with the effect of the increased temperature.
The modularity of the designed flow chemistry platform
makes it adaptable to continuous organic synthesis (Section S5).
The reaction in Scheme 1c was conducted at 35 °C using a total
volumetric flow rate of 250 µL/min, providing an irradiation time of
50 s. Crude reaction mixtures were collected over 30 minutes of
operation and showed complete conversion to 6 with a gas:liquid
ratio of 4:1 at 2.8 W and 37 W and a conversion of 99% with 2:1
at 37 W. The direct translatability of conditions from screening to
continuous synthesis without any measurable loss in performance
further demonstrates the unique advantages of this platform,
enabling simultaneous reaction discovery and optimization as
well as continuous scaled-up synthesis.
In conclusion, the reported experimental setup enables
material efficient screening and optimization of continuous (e.g.,
reaction time, LED power, temperature) and discrete (e.g.,
substrates) parameters associated with photocatalyzed reactions
using only 30 µL of the reaction mixture per experimental
condition (30 µL prepared, 15 µL injected). 150 reaction
conditions were explored using a total volume of only 4.5 mL.
Screening results are readily translated to continuous synthesis
at the same characteristic length scale and irradiation flux and
could be scaled-out using multiple reactors.
4
cd. Compared to the previously-reported batch reaction,[8]
reaction times using our developed flow chemistry platform are
substantially reduced (e.g., 16 hours versus 10 minutes for R =
CN). However, as shown in Figure 4, yields of product 4 for the
ethyl, methyl, methoxy, and fluoro substrates exhibit a significant
decrease with increasing residence time. The observed decrease
in the reaction yield might be explained by the substantially higher
2 2
oxygen pressure of our system (791 kPa O versus 21 kPa O in
[
8]
Zou et al. ) and the enhanced photon flux, both contributing to
over-oxidation of the phenolic product. All substrates reached
near 100% conversion.
The observed over-oxidation tendency is most pronounced
for the methoxy, methyl, ethyl, and fluoro substrates, but also
occurs in the cyano and chloro substrates. Online LC/MS analysis
reveals the emergence of an over-oxidized side product in all
cases except R = H. The observed trend is consistent with classic
Hammet substituent effects, which capture a combination of
inductive and resonance effects (Table S3).[
9]
The aluminum housing of the Teflon reactor in combination
with a thermoelectric plate allows for an accurate and systematic
study of the effect of reaction temperature, without the typical
confounding heating that results at high LED powers. This ability
is demonstrated via the photocatalytic oxidation of thiophenol (5)
to diphenyldisulfide (6) (Scheme 1c). This photo-oxidation
reaction is an attractive means of accessing disulfide compounds,
previously demonstrated in both batch and flow.[
Understanding of and control over the formation of disulfide
4e, 10]
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Acknowledgements
We thank the Novartis Center for Continuous Manufacturing for
funding this research. C.W.C. thanks the National Science
Foundation Graduate Research Fellowship Program for support
under Grant No. 1122374.
[
Keywords: photocatalysis • microreactors • high-throughput
screening • flow chemistry, droplet microfluidics
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