Photoredox catalysis under shear using thin film vortex microfluidics

Article abstract of DOI:10.1039/c5cc02153g

A microfluidic vortex fluidic device (VFD) operating in either confined or continuous mode is effective in high yielding photoredox reactions involving Rose Bengal, with short reaction times. This processing can be translated to multi-components reactions

Full text of DOI:10.1039/c5cc02153g

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Photoredox catalysis under shear using thin film vortex microfluidics†‡
Michael N. Gandy,a Colin L. Rastonb* and Keith A. Stubbsa*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
products. Thin films have a larger volume to surface area so
that the irradiating source becomes much more effective and
50 homogenous, approaching a uniform flux per molecule as the
liquid transverses the light source. We recently developed a
thin film microfluidic vortex fluidic device (VFD), which is
an efficient platform for preparing organic molecules,
controlling chemical reactivity and selectivity8 and has been
55 used in a wide variety of synthetic applications,16ꢀ18 along
with protein folding19 and materials processing.20
5
A microfluidic vortex fluidic device (VFD) operating in either
confined or continuous mode is effective in high yielding
photoredox reactions involving Rose Bengal, with short
reaction times. This processing can be translated to multi-
components reactions, also with significantly reduced
10 processing times relative to batch processing and channel
microfluidic processing, with comparable or improved yields.
Developing new synthetic methods lies at the heart of organic
chemistry. They require the detailed understanding of a
chemical reaction at the molecular level for gaining access to
15 new molecules for therapeutic or materials applications. In
addition, they require developing new technologies that allow
for the rapid synthesis of such molecules. Flow chemistry has
been developed to meet this challenge, and is now common
place in industry, having advanced since the advent of
20 smallerꢀsized reactors that allowed researchers to work in
laboratory settings.1,2 Advantages of the use of flow chemistry
lie in controlling chemical reactions at various levels
including reagent quantities, surface area of reactions and the
ability to automate the processes.3 The microfluidic
25 platforms4ꢀ11 used in flow chemistry are successful in the
synthesis of a wide variety of molecules. In terms of their
design they commonly rely on the use of channels6,9,12 where
there is laminar flow, or more recently rotating surfaces8,11
where dynamic thin films are not restricted to diffusion
30 control of the reactions.11
The utility of the VFD relates to the generation of a thin
film in the rapidly rotating reaction tube at a tilt angle above
the horizontal position8 with the thickness of the thin film
60 exquisitely controlled primarily by varying the speed of
rotation of the tube and the tilt angle. The VFD is usually
operated in one of two modes, the so called confined mode for
a finite volume of liquid and the continuous flow mode.8 For
the confined mode the mixing is dependent on
65 Stewartson/Ekman layers20 and for continuous flow jet feeds
direct reacting liquids to the base of the tube where there is
intense microꢀmixing as the liquids move in the tube.
Furthermore the VFD is robust and simple to operate and
maintain, and does not suffer from clogging which can occur
70 for flow chemistry using channel reactors.3,9 Herein we
describe the use of the VFD as part of our program towards
developing efficient synthetic protocols for organic reactions,
in performing photoredox reactions in both the confined and
continuous flow modes, with an emphasis placed on the use of
75 this device as a simple flow reactor. We note that the confined
mode is suitable for small scale processing, and the
continuous flow mode addresses scalability, allowing higher
volume processing using parallel arrays of the microfluidic
device, as for channel based microfluidic systems.9 The
80 application of the VFD centred on the use of organic dyes
because of their green chemistry credentials. Recently it has
been demonstrated that such molecules, especially Eosin Y
and Rose Bengal (RB), can be used in photoredox reactions,21ꢀ
One research area that has benefited from the use of flow
methodology is that of photoredox chemistry.13,14 Coupling
the high throughput nature of channel flow reactors with the
mild reactions conditions invoked in photoredox chemistry
35 has resulted in
a large number of different chemical
transformations having been achieved using this technology.15
An interesting paradigm for photochemistry under flow
would be the use of devices which incorporate intense microꢀ
mixing in thin films of the reaction medium. Here the thin
40 films would allow for (i) rapid heat transfer and no large
temperature isotherms, (ii) uniform mixing of reagents, and
(iii) introducing new compounds quickly without disturbing
the concentrations of the reagents in an unbiased manner.
Applying such thin film processing in photoꢀbased reactions
45 overcomes a fundamental problem associated with batch
processing where the irradiating source is impeded by the bulk
solution which can result in reduced yields and mixtures of
24
with multiple groups demonstrating their utility in both
85 batch and channel based flow chemistry conditions.13,25ꢀ38
Initially we chose to assess the applicability of using the
VFD in CꢀC and CꢀP bond forming reactions using
tetrahydroisoquinoline derivatives as substrates in model
reactions noting that these types of reactions have been
90 conducted previously26,29,30,32,35 using other conditions.
Molecules based on the tetrahydroisoquinoline scaffold are
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important synthetic intermediates to a variety of important
compounds in medicinal chemistry, especially in cancer and
antibiotic discovery.39 We chose initially to use the confined
mode of operation of the VFD to first demonstrate if the
reactions could be carried out in the device, and to then refine
the processing parameters as a prelude for the continuous flow
mode of operation. All the studies were conducted using a 10
mm OD borosilicate glass NMR tube.
55 Table 2 Synthesis of various coupling partners using the VFD
operating at 4000 rpm and 45° tilt angle at room temperature in
confined mode for 75 minutes. All reactions were conducted in
triplicate with the average shown. Errors were within ±2%. Literature
yields for other flow chemistry reactions are shown in brackets.26,30,
5
35,36
60
DEM = Diethyl malonate, DEP = Diethyl phosphite *=batch
reaction yield.
10
Coupling
Partner
Yield
Entry Substrate
R1
Product
15 Scheme 1 Model reaction for investigating the utility of the VFD for
photoredox reactions in the confined mode.
(Lit. Yield)
R1
CH3
OMe
Br
R2
At the outset we used Nꢀphenyltetrahydroisoquinoline and
nitromethane as their reaction enjoys high yields and has been
20 widely used as a model visible light catalysed reaction,
79(85)35
81(86)35
83(89*)26
78(82*)26
72(78)30
1
2
CH3
OMe
Br
CH3NO2
CH3NO2
CH3NO2
EtNO2
EtNO2
EtNO2
EtNO2
ProNO2
ProNO2
ProNO2
ProNO2
TMSCN
TMSCN
TMSCN
TMSCN
DEM
CH2NO2
CH2NO2
utilising
both
metalꢀbased
catalysts13,40ꢀ42
and
organocatalysts.26,29,30 To optimise the operating parameters
of the VFD, we measured the percentage conversion for the
model reaction under various settings of tilt angle and
25 rotational speed. In all cases the reaction was deemed
complete after only 90 minutes and overall this established
that operating the VFD at 4000 rpm and 45° produced the
highest conversion, at 78% yield.
3
CH2NO2
4
H
H
MeCHNO2
MeCHNO2
5
CH3
OMe
Br
CH3
OMe
Br
6
MeCHNO2 74(97*)36
76(64)30
7
MeCHNO2
71(95*)26
EtCHNO2
8
H
H
30 Table
1
Percentage conversion for the reaction between Nꢀ
phenyltetrahydroisoquinoline and neat nitromethane in the presence of
Rose Bengal and green LED light for 90 min, when varying the rotational
speed and tilt angle of the VFD. All reactions were conducted in triplicate
with the average shown. Errors were within ±2%.
9
CH3
OMe
Br
CH3
OMe
Br
EtCHNO2
EtCHNO2
EtCHNO2
CN
76(91*)36
77(95*)36
74(91*)36
83(87)35
81(77)35
69(64)35
87(75)35
81(71)35
74(53)35
77(51)35
78(55)35
81(59)35
82(56)35
84(60)35
71(56)35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
—— Rotational Speed (rpm) ——
Tilt Angle (°)
H
H
2000
57%
25%
4000
77%
78%
7000
59%
77%
15
45
CH3
OMe
Br
CH3
OMe
Br
CN
CN
75
18%
57%
60%
35
CN
Although the model reaction has been previously conducted
using only nitromethane as solvent,26,36 other workers35 have
also included water and acetonitrile as coꢀsolvents,
presumably to improve the solubility of the RB. In our hands,
H
H
CH(CO2Et)2
CH(CO2Et)2
CH3
OMe
Br
DEM
CH3
DEM
OMe CH(CO2Et)2
40 to achieve complete dissolution of the RB in a reaction
medium containing water and acetonitrile as coꢀsolvents, it
was necessary to reduce the final concentration of RB from 5
mol% to 1 mol%. Remarkably, using this solution together
with the optimised VFD parameters, we found that we could
45 effect 98% conversion and 80% isolated yield after
chromatography with a significantly reduced reaction time of
75 min. Compared to literature flow reactor conditions35,
where the reaction was run for 5 h for a yield of 92%, these
optimised conditions are able to effect a >3ꢀfold reduction in
50 reaction time with comparable yields as well as a 80%
reduction in catalyst loading.
DEM
Br
H
CH(CO2Et)2
PO(CO2Et)2
PO(CO2Et)2
PO(CO2Et)2
PO(CO2Et)2
H
DEP
CH3
OMe
Br
DEP
CH3
OMe
Br
DEP
DEP
With suitable reaction conditions established using the
65 reaction of Nꢀphenyltetrahydroisoquinoline and nitromethane
as a model, we expanded the repertoire of coupling partners to
demonstrate the widespread utility of the method (Table 1). In
2
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all cases the yields were comparable to literature preparations
of the respective compounds for other flow chemistry
reactants contributes to the product(s), and this type of
reaction has had great success in medicinal chemistry.43
conditions, but achieved in a considerably shorter time, as 65 Specifically the Ugi multicomponent reaction has been shown
demonstrated for nitromethane.
to be effectively mediated using an organic dye under
photoredox conditions. Unfortunately, low yields and long
reaction times, in both batch and channel based flow
processing, limit further advances using such processing. The
5
With these results in the confined mode in hand we sought
to extend the strategy to the continuous mode of operation of
the 10 mm glass tube VFD. Of note is that the reaction time
used in the confined mode (75 minutes) was highly 70 starting material N,Nꢀdimethylaniline was incubated with 4ꢀ
commensurate with a flow rate of 0.05 mL/min that can be
toluenesulfonylmethyl isocyanide in the presence of water
under the confined mode of operation of the VFD, using the
same optimised parameters described for the preparation of
10 delivered by the jet feeds in the VFD and so this results in a
similar residence time for the reaction mixture.8 Again using
Nꢀphenyltetrahydroisoquinoline and nitromethane as a model
the tetrahydroisoquinoline derivatives
(Table 1).
example we exposed a working solution of the reagents used 75 Interestingly, while the reaction proceeded at a lower rate than
in the confined mode experiments to the continuous mode
15 conditions. Fractions of the reaction mixture were then
collected and gratifyingly we found that high conversion had
indeed been achieved (Figure 1). Of note is that the initial
for the tetrahydroisoquinolineꢀbased reactions, it was
complete in a far shorter time period than what has been
reported previously for batch and channel flow chemistry
processing, indeed up to 300% faster.35 More importantly, the
fractions have a higher conversion than fractions collected 80 yields of the reactions were greater or at least comparable to
later, implying that there is a need for establishing a steady
20 state conversion of the starting material. Based on these
results the flow rate was increased to ascertain what effect this
would have on the percentage conversion. An increased flow
rate would result in a reduced residence time and so if a
reduced conversion was observed it would establish the
25 practical lower level flow rate required for conversion.
Indeed, at a flow rate of 0.1 mL/min there was a reduction in
conversion which demonstrates that the residence time of 75
minutes is critical to the conversion. We then expanded the
study to Nꢀphenyltetrahydroisoquinoline and other coupling
30 partners that were used earlier and saw similar results (See
Supporting Figure). Overall this demonstrates the utility of the
VFD in both modes of operation of the device for preparing
these types of compounds.
those reported previously.
Table 3 Synthesis of various coupling partners using the VFD operating
at 4000 rpm and 45° tilt angle at room temperature in the confined mode
85 for 12 hours. All reactions were conducted in triplicate with the average
shown. Errors were within ±3%. Literature yields for other flow
chemistry reactions are shown in brackets.35, 37 *=batch reaction yield.
Yield
Entry Substrate 1 Substrate 2
Product
(Lit. Yield)
35
40
45
R1
H
R2
CH2Ts
R1
H
R2
83(79)35
72(51)35
79(83)35
44(60)35
53
1
2
CH2Ts
CH2Ts
Me
Br
H
CH2Ts
Me
Br
H
3
CH2Ts
CH2Ts
4
C4H9
C4H9
5
Me
Br
H
C4H9
Me
Br
H
C4H9
6
C4H9
C4H9
48
80(78)35
73(68*)37
70
7
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2Ph
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2Ph
50 Figure
1 Synthesis of 1ꢀnitromethylꢀ2ꢀphenyltetrahydroisoquinoline
8
Me
Br
H
Me
Br
H
using the VFD operating at 4000 rpm and 45° tilt angle at room
temperature in the continuous flow mode. Fractions (2 mL) were
collected in a continuous fashion from when the reaction mixture begun
to elute from the device. All reactions were conducted in triplicate with
55 the average conversion shown (errors within ±2%) as determined using
1H NMR.
9
41(57)35
52
10
11
12
Me
Br
CH2Ph
Me
Br
CH2Ph
With the success of these reactions we turned our attention
to other types of reactions for translational purposes. A recent
60 area of chemical research that has benefitted from the use of
photoredox catalysis involves multicomponent reactions.35
These involve multiple reactants (≥3), where each of these
50(57*)37
CH2Ph
CH2Ph
90
We note that the use of the continuous flow mode of
operation of the VFD is not viable for these reactions as the
lowest practical flow rate deliverable does not result in
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substrate conversion.
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relatively cheap, is an efficient and useful device for
photoredox chemical reactions using organic dyes. Due to the
nature of the VFD in that the rotational speed and tilt angle of
the tube can be varied, thin films can be generated which are
highly effective in photochemical reactions, allowing for rapid
heat transfer, intense microꢀmixing and homogenous
5
70
75
80
85
10 irradiation. The VFD is effective for these types of reactions
in both the confined and continuous flow modes of operation.
The latter is extremely important as conventional channel
flow chemistry equipment is expensive to purchase, operate
and maintain, and thus the VFD potentially provides a viable
15 alternative, with significantly improved outcomes of the
reactions. Matching the residence time of a liquid under
continuous flow mode to be equivalent to the processing time
for the VFD operating under confined mode (75 minutes), by
adjusting the flow rate, results in similar yields. This is
20 consistent with the shear arising from the film instability for
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aSchool of Chemistry and Biochemistry, The University of Western
Australia,
Crawley,
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6009,
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E-mail:
105
35 keith.stubbs@uwa.edu.au
bCentre for NanoScale Science and Technology, School of Chemical and
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