a laser driven flow chemistry platform for scaling

A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light Kaid Harper, Eric Moschetta, shailendra Bordawekar, steven wittenberger
Submitted date: 05/09/2018 • Posted date: 06/09/2018 Licence: CC BY-NC-ND 4.0 Citation information: Harper, Kaid; Moschetta, Eric; Bordawekar, shailendra; wittenberger, steven (2018): A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light. ChemRxiv. Preprint.
Visible light-promoted organic reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solutions exist to employ these reactions for multi-kilogram production. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high intensity laser to drive photochemical reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer-Lambert law as a guideline to optimize catalyst concentration and reactor depth for maximum throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochemical reactions.
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Reactions with Visible Light
Kaid C. Harper, Eric G. Moschetta, Shailendra V. Bordawekar, Steven J. Wittenberger
Affiliations:
1 North Waukegan Road, North Chicago, IL 60064
Abstract: Visible light-promoted organic reactions can offer increased reactivity and selectivity
via unique reaction pathways to address a multitude of practical synthetic problems, yet few
practical solutions exist to employ these reactions for multi-kilogram production. We have
developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high
intensity laser to drive photochemical reactions at unprecedented rates in continuous flow,
achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses
the Beer-Lambert law as a guideline to optimize catalyst concentration and reactor depth for
maximum throughput. This laser CSTR platform coupled with the rationale for design can be
applied to a breadth of photochemical reactions.
The use of visible light as an energy source in organic synthesis has expanded rapidly over the
past decade driven by the use of photocatalysts that are capable of harnessing photonic energy to
generate new chemical bonds. 1-7
Photocatalysts that absorb in the visible spectrum have been
applied to a wide variety of synthetically useful chemical transformations, resulting in
improvements to existing transformations and also identification of new transformations that
have opened up new possibilities in synthetic route design. These new photochemical
methodologies often exhibit enhanced reactivity, enhanced selectivity, improved tolerance for
molecular complexity, and are well suited to pharmaceutical development at both the discovery
and development stages. However, implementation of photochemistry at multi-kilogram scale
has been hindered by several inherent challenges associated with the attenuation of light as
dictated by the Beer-Lambert law. Herein, we disclose the design and successful evaluation on
scale of a modular continuous flow reactor, a laser driven continuous stirred tank reactor (CSTR)
that was designed using an understanding of the impact of the Beer-Lambert law on the
photochemical process.
The primary challenge in scaling photochemical reactions is addressing the Beer-Lambert law,
which dictates the depth to which light can penetrate a solution. Rearranging the Beer-Lambert
law in terms of path length L (Eq. 1), transmittance T, concentration of the absorbing species c,
and its molar extinction coefficient , demonstrates a limiting exponential relationship. 8
= − ()
(Eq. 1)
In photochemical reactor design, flow chemistry has been universally identified as the solution to
overcome the attenuation of light by providing reactor geometries with increased surface area-to-
volume ratios, allowing increased illumination of the reaction solution relative to conventional
batch reactors. 9-12
Among photochemical flow reactors, the plug flow reactor (PFR) design of
Booker-Milburn has been favored, composed of semi-transparent tubing in combination with an
array of LEDs or UV lamps. 13,14
Reactors of this type have been applied across academia and
industry with excellent success for gram-scale reactions. 15-30
However, extension of these plug
flow reactors to kilogram-scale production remains a significant challenge. One approach that
has been pursued involves increasing the number of identical reactors operating in parallel,
thereby increasing the overall throughput. 31,32
While this approach is tenable in some
circumstances, it also presents several operational and practical challenges, particularly in the
highly regulated manufacture of pharmaceuticals. The other approach is to extend the length of
the reactor to increase the volume/throughput, which necessitates a more elaborate lighting array.
Efforts by the Stephenson group and others have demonstrated some limited scale-up with this
design; however, a key challenge remains the translation of results between bench-scale reactors
used for reaction optimization to production-scale reactors. 27,33,34
The geometry of the lighting
array and the reactor both significantly impact the performance of the reactor and subtle changes
in this geometry can lead to dramatic effects on the reactor throughput. Chemical actinometry, a
method for relating the rate of reaction to the rate of photon absorption in a reactor, can correlate
reactor performance across scales, but requires time, effort, and equivalent amounts of material
to generate accurate calibrations. 35-37
LED-based reactors are generally challenging to scale due
to the diffusive emission of LEDs, which dictates they must be array in close proximity to the
tubing to illuminate the reactive fluid. As a result, the heat that the LEDs generate may
negatively influence the reaction, requiring additional engineering solutions at scale. In general,
the engineering challenges inherent to building an LED-based tubular flow reactor capable of
multi-kilogram throughput necessitate construction of a fixed volume reactor and a fixed light
source, thereby significantly limiting the modularity and adaptability benefits of flow chemistry.
After studying the scalability of plug flow photoreactors, we concluded that these reactors would
not meet our adaptability requirements and accordingly directed our efforts to developing a more
modular system.
Our studies indicated that higher intensity light sources would lead to increased rates of reaction,
thereby increasing throughput and yield. 38
The Beer-Lambert law only dictates the fraction of
incident light that is absorbed, not the total amount of light, so we reasoned that using higher
intensity light sources would increase process throughputs if coupled to an appropriately
designed reactor. Our efforts to find higher intensity monochromatic light sources led us to
employ laser diodes in photochemical reactions. Continuous wave lasers have only been utilized
in limited context within photochemistry, particularly in conjunction with microreactors, and
only at low power (10-50 mW), which is comparable to the light emitted by a single common
LED. 39
Comparatively high power diode lasers (up to 6 W) are readily available in common
wavelengths and we applied these lasers to a number of reactions of interest and immediately
observed vastly improved rates of reaction. 40
The benefits of such lasers include the ability to
directly measure the output power, the relative ease of directing the light into the reaction
mixture, coherence of the light, and the ability to shape the beam to fit the reactor.
We compared lasers to other light sources in relevant photochemical reactions and generated
several broad observations that informed our efforts to develop a versatile platform for visible
light photocatalysis. 41
The most impactful observation was the universal dependence of the rate
of reaction on the intensity of the light source. Similar results have also been reported by
MacMillan and coworkers across a separate set of reactions. 42
These combined results suggest a
general trend across catalysts and transformations, which directed us to apply even higher
powered lasers.
To explore the potential of higher powered light sources, a 25 W 450 nm fiber coupled laser
system was fit with an adjustable beam expander. A recently reported C-N coupling reaction
was selected as a model reaction (Figure 1A) as we viewed it as representative of an increasing
number of metallaphotoredox cross-coupling reactions, which are of particular interest in the
pharmaceutical industry. 43-52
Preliminary kinetic investigation in batch revealed apparent zero-
order kinetics up to 87% conversion, followed by an apparent shift in the rate-determining step.
The rate of reaction was not affected by variations in concentration of DABCO or pyrrolidine,
but did depend on photocatalyst, Ni, and aryl bromide concentrations. In preparation for
eventual scale-up, the optimal reaction concentration was determined to be 0.8 M in aryl
bromide, beyond which DABCO-HBr salt precipitation became a limiting factor.
Under optimized conditions, we first examined the effect of photocatalyst concentration across
two orders of magnitude (0.05 to 6 mM), holding the laser configuration and liquid depth (5 cm)
constant while measuring the rate of reaction. Figure 1B shows the optimal catalyst
concentration to be 0.2 mM (0.025 mol %) as well as two different rate behaviors around this
optimal point. At concentrations lower than the optimal concentration, traditional kinetic
behavior is observed, implying that catalyst quenching is the rate-limiting step. At catalyst
concentrations higher than the optimal point, the rate of reaction declines exponentially, a
relationship which appears to be counterintuitive to the general principles of catalysis where
increased catalyst loadings should result in faster rates. However, the Beer-Lambert law states
that light attenuates exponentially as the catalyst concentration (the absorbing species) increases.
These differences in rates arise from variations in the effective concentration of quenching
species relative to that of the excited state catalyst. At the highest catalyst concentrations, 99.9%
of the incident light is absorbed at 1 cm of depth. Hence, all of the excited catalyst is contained
in 20% of the total volume, but the quenching species is distributed uniformly across the entire
volume, creating a lower proximal ratio of activated catalyst to quenching species (presumably
the Ni-Aryl species). At the optimal catalyst loading, the light penetrates to the bottom of the
reactor (5 cm depth) and the optimal ratio of excited state catalyst to quencher is achieved,
leading to the interesting observation that while the rate of reaction remains constant through
high conversion, increasing the concentration of quencher can impact the rate. This correlation
to the Beer-Lambert law can be powerfully applied to design photochemical systems where the
solution depth (path length) and catalyst concentration can be adjusted relative to each other and
adapted to process constraints, whether those constraints are on catalyst loading or reactor
geometry. Beyond the context of the high intensity laser, we have observed this same trend
where decreasing catalyst concentration up to a certain point leads to increased rate of reaction,
independent of the light source used. 38,53
Indeed, at the beginning of our evaluation, the system
was designed based on the Beer-Lambert law calculation for 0.05 mol % of photocatalyst to give
maximum absorption at a reaction depth of 5 cm. We attribute the difference in observed
catalyst concentration to that determined from the Beer-Lambert law to significant solution
darkening which occurs during the reaction which is equivalent to 50% increase in absorbance at
450 nm Figure 1C.
Figure 1. A) The C-N coupling reaction used with the optimized conditions. B) Plot of the
initial rates of reaction at several different catalyst concentrations with the proposed exponential
relationship shown as a dotted line. C) Time course plot of the C-N coupling reaction showing
the conversion of aryl bromide in red and the solution darkening effect in blue.
Initially surprised by this counterintuitive trend, we sought to explore the generality of this
principle in other reactions. We evaluated the effect of catalyst concentration in two other
reactions of interest (Figure 2). We performed these reactions at smaller scale with less powerful
diode lasers and observed the same general trend where the fastest rates of these very different
reactions could all be directly attributed to the concentration designed to give 99% absorbance of
the incident light at the predetermined, fixed reaction depth. These combined results strongly
indicate that optimal reaction performance in terms of rate is directly correlated to photocatalyst
concentration which can be determined entirely from the Beer-Lambert law based on the vessel
used and not the associated chemical transformation.
A)
B) C)
Figure 2. A) Initial rates as a function of catalyst concentration demonstrating a Beer-Lambert
law relationship in decarboxylative C-C bond formation. B) Initial rates as a function of catalyst
concentration as another demonstration of the Beer-Lambert law in the anti-Markovnikov
addition of carboxylic acids to alkenes.
This demonstration of the impact of the Beer-Lambert law on the rate of reaction led us to
consider alternate flow reactor designs. The absolute molar concentrations for common
photocatalysts result in complete extinction of light within millimeters of liquid depth, especially
for catalysts with molar extinction coefficients orders of magnitude higher than Catalyst 1 (567
M –1
cm –1
) as used in the C-N coupling. 7 The extremely small extinction depth at commonly
employed catalyst concentrations has led to the notion that smaller reactors with smaller cross
sections and increased surface areas are the only solution to overcoming the attenuation effect.
Perhaps due to its counterintuitive nature, little consideration has been given to optimizing
reactors with larger cross-sectional areas and decreased photocatalyst concentrations; however,
our results suggested a reactor of this type would be ideal when coupled to a high intensity light
source.
Another key variable we explored was the effect of laser output power on the reaction rate by
varying the output from 10 to 26 W. We hypothesized that by optimizing the catalyst
concentration and solution depth using the Beer-Lambert law, the reaction rate should increase as
the power emitted by the laser increases as long as quenching of the excited state remains the
rate-limiting step. At a depth of 5 cm, a linear relationship was observed between rate and power,
which is described in terms of power density (W/cm 2 )(Figure 3A). This relationship is the most
direct evidence that the rate-limiting step is quenching of the excited state and that quenching is
limited only by concentration of catalyst in the excited state. Increasing the excited state
concentration simply by bombarding the reaction with increasing numbers of photons can drive
the reaction to significantly faster rates. Applied to a flow reactor, this relationship is
extraordinarily powerful because it implies that the reaction throughput can only be increased by
increasing both the reaction volume (as a function of surface area) and the power of the light, if
the reactor depth and catalyst concentration are already optimized using the Beer-Lambert law.
To test this relationship as a design principle, identical conditions were evaluated in larger and
smaller diameter reactors resulting in two different power densities, while maintaining the
optimal 5 cm depth. The rates were measured and compared to those predicted based on the
relationship in Figure 3A. The results shown in Figure 3A clearly demonstrate the predictive
power of such a relationship, with the error between the predicted and measured rates being less
than 5%.
While the correlation in Figure 3A was extrapolated well outside the experimental data;
theoretically, at some power density, a maximum concentration of excited catalyst must be
achieved and a corresponding shift in the rate-determining step would be indicated by a break in
linearity in the power density relationship. Equipment power limitations prohibited further
exploration in the C-N coupling; however, such a deviation in linearity was observed in our
exploration of the anti-Markovnikov addition to alkenes reported by Nicewicz and coworkers. 54-
56 Performing a similar variable power experiment under the conditions shown in Figure 3B
resulted in a deviation where increasing power density no longer resulted in increased rate. We
interpret this deviation in linearity to indicate the maximum photon absorption rate where the
rate-limiting step is no longer quenching of the excited state. This type of relationship can also
inform reactor design and indicates the optimal power density where increasing the power output
from the laser no longer improves throughput. Where this type of behavior is observed, the
reactor size can be increased as long as this power density is maintained, providing increased
throughput.
Figure 3. A) Correlation between initial rates in the C-N coupling and power density of the laser
source where the standard reactor employed was 6.5 cm diameter (167 mL total volume), the
large reactor was 8 cm (250 mL total volume) and the small reactor was 5 cm in diameter (100
mL). B) Example reaction where the rate/power correlation breaks down providing an optimal
power density for scale-up.
A) B)
With these fundamental studies as guides, the optimal flow reactor was designed to implement
the high-powered laser as the light source. However, to incorporate the laser as a light source
and to take advantage of the concepts detailed above, a CSTR became an obvious choice (Figure
4). CSTRs are better suited to handling solids as opposed to tubular or plug flow reactors. Most
importantly, a simple CSTR design enables the easy adaptation of our laser light source and
provides modularity in reaction vessel choice, enabling the use of common laboratory
equipment. For the C-N coupling reaction, the smaller diameter vessel (100 mL reactor) which
was employed in the power density studies was modified into a CSTR. Using a simple CSTR
design, the depth of the reactor could be controlled at 5 cm by the reactor outlet, the optimal
depth based on the Beer-Lambert law for our desired catalyst concentration (Figure 4). A flow
rate of 5 mL/min was dictated by the desired residence time (the volume divided by the flow
rate), which was conservatively set at 20 minutes. This residence time was determined by
Levenspiel analysis of the reaction kinetics and indicated the optimal throughput would be
achieved at 90% conversion. 5758
Figure 4. Reaction and reactor schematic for the laser driven CSTR.
The CSTR described above was run for a total of 32 hours at steady-state (Figure 4). The system
proved remarkably stable with the laser giving precise power output over the entire course of
operation. In total, 1.85 kg of aryl bromide was processed, achieving 89% conversion at steady-
state, which corresponded nicely with the projected output given by the Levenspiel analysis.
Isolation of the product produced 1.54 kg, corresponding to a throughput of 1.2 kg/day and 85%
adjusted yield with >99% purity. Remarkably, this excellent throughput was achieved in a 100
mL reactor in a common fumehood and required only 2.22 grams of photocatalyst. Inspection of
Inlet Pump
100 mL
Material Product Beam
Fiber Optic Laser
the reactor after run completion revealed a fine precipitation or coating of the reactor walls. This
minor fouling did not affect the measureable reactor performance. However, such fouling is
commonly observed in tubular flow reactors where it leads to decreased reactor performance by
blocking the light.
Overall, the modular design of the laser CSTR lends itself to facile scalability and flexibility.
Limitations in our equipment prevented us from applying a multistage CSTR; however, our
Levenspiel analysis of the reaction kinetics allows us to project a series of three identical volume
(3 x 100 mL) CSTRs requiring three 25 W lasers that would be capable of 99% conversion and
6.5 kg/day throughput. Similarly, higher powered lasers (1000 W 450 nm lasers are
commercially available) could also be applied in the same system to give even greater
throughput, providing a clear path forward for commercialization of photochemical processes
that use visible light. Use of a fiber coupled laser allows reactor configuration flexibility,
potentially enabling gas-liquid flow and sub-zero reaction temperatures. Perhaps more
importantly, through the application of lasers, the key relationship between light source and
reaction rate can be determined, providing the foundation for successful scale-up.
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50 Zhao, W., Wurz, R. P., Peters, J. C. & Fu, G. C. Photoinduced, Copper-Catalyzed
Decarboxylative C–N Coupling to Generate Protected Amines: An Alternative to the
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57 See the Supporting Materials for a detailed discussion of how this analysis was
performed.
58 Levenspiel, O. Chemical Reaction Engineering, 3rd Edition. 3rd edn, (John Wiley &
Sons, 1998).
Acknowledgments: The authors would like to thank Anuj Verma, Steve Richter, Moiz Diwan,
Travis Dunn, Michael Tudesco, Andrew Radosevich, Jeffrey Kallemeyn, Jianguo Ji, Shashank
Shekhar, Elizabeth Swift, David Barnes, Dennie Welch, Nathan Ide, Dan Tao and Patrick Brady
for helpful discussions and preparing the manuscript.
The authors declare no competing financial interests. The design, study conduct, and financial
support for this research was provided by AbbVie. AbbVie participated in the interpretation of
data, writing, reviewing, and approving the publication. K.CH. E.G.M and S.V.B. are AbbVie
employees.
All data is available in the main text or the supplementary materials.
Author Contributions: K.C.H. and E.G.M designed and executed the research and contributed
equally to the work. S.V.B. and S.J.W. supervised the research.
Author Information: The authors declare no competing interests. Correspondence and
requests for materials should be addressed to [email protected] and
[email protected]
download fileview on ChemRxivA Laser Driven Flow Chemistry Platform for Scaling Photo... (1.10 MiB)
Reactions with Visible Light
Kaid C. Harper, Eric G. Moschetta, Shailendra V. Bordawekar, Steven J. Wittenberger
Correspondence to: [email protected], [email protected]
This PDF file includes:
Beer’s Law Derivation .........................................................................................................2
The Anti-Marknovnikov Hydroamination Comparison ......................................................5
The Anti-Marknovnikov Hydroacetoxylation Comparison .................................................7
The Pyrazole Synthesis Comparison ...................................................................................9
C-N Coupling Reaction Order Experiments ......................................................................18
25 W Laser System General Details ..................................................................................23
Catalyst Concentration Rate Experiments .........................................................................24
Solution Depth Rate Experiments ......................................................................................26
Laser Power Density Rate Experiments Anti-Markovnikov Hydroacetoxylation ............33
C-N Coupling Reaction Darkening Experiment ................................................................35
Laser CSTR Design and Evaluation ..................................................................................36
Compound Characterization ..............................................................................................44
References ..........................................................................................................................46
Beer’s Law Derivation The logarithmic dependence of the transmittance of light, T, on the depth to which the light
penetrates, L, was presented as one representation of Beer’s law in the main text. Beer’s law is
more commonly expressed in a linear form using absorbance, A, for ease of experimental and
computational use:
= (Equation S1)
As before, ε is the molar extinction coefficient of the absorbing species and C is the molar
concentration of the absorbing species. The logarithmic relationship is apparent through the
definition of the relationship between absorbance and transmittance:
= − log (Equation S2)
Substituting the expression for absorbance into Equation S1 into Equation S2 and solving for L
gives
General Details for the Light Source Comparison
Laser Reaction Configuration
6W Laser diodes were purchased from Amazon (ASIN = B014NN3AYW and
B01H93UXWA). These diodes were equipped with a heat sink (ASIN = B017BWKB2Q). The
laser was connected to DC power source by alligator clips. The G2 lens was adjusted such that
the laser produced a rectangle pattern 2.5 cm x 0.1 cm at a distance of 8 cm from the laser. The
reactions were set up in a 40 mL vial with a Teflon coated magnetic stir bar. Reactions were
designed to have 5 mL of total volume which was ~1 cm of liquid depth. The pre-adjusted laser
was placed at the top of the 40 mL vial creating 8 cm of distance from the lens to the surface of
the liquid. Reactions were stirred at 300 rpm in open air with temperature control provided by an
equilibrated aluminum block. The reactions were illuminated by 450 nm and 530 nm diode
lasers where the output power was controlled at the DC power supply. In the reported examples,
the same laser, power supply, and power settings were used to ensure homogeneity. The power
setting was 1.5 Amps which corresponded to 1.6 Watts of output. The output was measured by a
Thor Labs PM160T-HP power meter. 1.6 Watts was identified as the equilibration point for the
laser diodes with the afore mentioned heat sinks, as higher input amperages led to increased
heating and equivalent power levels. For the comparison experiments, temperature control was
maintained via aluminum block or a cold plate; however, this temperature control did not
compensate for variation due to the intensity of the light source.
Figure S1.
Laser diode with DC power supply (left), a scheme of the laser irradiating a reaction
mixture in a vial (center), and an image of the laser irradiating a solution of photocatalyst (right).
LED-Tubular Flow Reactor Assembly
Each tubular reactor was built from a 34/45 vacuum trap from Ace Glassware. A length of
0.125 in. OD PFA tubing from IDEX was wrapped around the outer body of the trap and held in
place with electrical tape. A flexible strip of LEDs was wrapped around the inner tube of each
trap to ensure the tubular flow reactors were fully illuminated. The power cord and extension
cable for the LED strips were connected and fed through the inner tube of the trap. The 450 nm
blue LEDs were obtained from Amazon (Aquatic Commitment) and the 525 nm green LEDs
were obtained from Super Bright LEDs Inc. The outer body of each trap was clamped in place
and immersed in a water bath that was connected to a chiller to control the temperature inside the
tubular reactor. The reactants were pumped into the reactor using a Harvard PHD 2000
programmable syringe pump and syringes with Luer Lock fittings (either glass gas tight 50 mL
syringes from SGE or 50 mL plastic Norm Ject syringes, depending on material compatibility).
The syringes were connected to a PEEK Y-mixer using Luer Lock fittings and 0.125 in. tubing
(all from IDEX) and fed into each reactor. The general scheme of the tubular flow reactors and
images of each reactor with LEDs are shown in Figure S2.
Figure S2.
A) Scheme of tubular flow reactor setups and actual configurations with B) blue LEDs and
C) green LEDs.
CFL Reaction Configuration
CFL reactions were performed under identical conditions to the laser configuration
except that a GE 23 Watt (input power) helical compact fluorescent bulb was used. The bulb
was placed 7 cm away from the edge of the vials used. The temperature of these reactions was
controlled by hot/cold plate and not in an aluminum block to allow direct illumination of the
reaction.
The Anti-Marknovnikov Hydroamination Comparison(1)
Laser
To a 40 mL vial with a 1 cm cross stir bar was added solid Ir[dF(CF3)ppy]2(dtbbpy)
(Catalyst 1) (1.12 mg, 1 μmol, 0.001 equiv.), 100 mg biphenyl (internal standard). This was
dissolved in 4.1 mL toluene (note: dissolution required sonication for 30 minutes at 40 °C).
Once completely dissolved, 2-methyl-2-(vinyloxy)propane (0.584 mL, 4.99 mmol, 5 equiv.) was
added by calibrated pipet followed by benzyl piperazine-1-carboxylate (0.194 mL, 0.999 mmol,
basis charge). Trip-thiol (0.110 mL, 0.499 mmol, 0.5 equiv.) was also added by calibrated pipet
for a total volume of 5 mL. The solution was allowed to stir with nitrogen sparging at 23 °C for
10 minutes. The nitrogen sparge was removed, a 0 minute sample was taken, and the solution
placed directly below the laser diode housed in a heat sink. The temperature was allowed to
equilibrate at 25 °C and the reaction illuminated. Time points were taken by turning off the
laser, removing a 5 μL aliquot and diluting it in 2 mL of acetonitrile and illuminating the reaction
once again. The reaction was monitored for 30 minutes. At the end of the time course, the
internal reaction temperature was recorded at 27.2 °C and the laser power was measured at 1.61
W. Samples were analyzed by HPLC and the conversion of the starting material at each time
point is reported in Table S1.
LED Flow Reactor
In a clean amber bottle, benzyl piperazine-1-carboxylate (4.38 mL, 22.70 mmol, 1 equiv.),
2-methyl-2-(vinyloxy)propane (13.26 mL, 113 mmol, 5 equiv.), Catalyst 1 (25 mg, 0.023 mmol,
0.001 equiv.), and 2,4,6-triisopropylbenzenethiol (2.508 mL, 11.35 mmol, 0.5 equiv.) were
combined and dissolved in toluene (113 mL) using a sonicator. A 50 mL syringe was filled with
the solution and secured in the syringe pump. The solution was flushed through the tubing (4.83
mL total volume, 450 nm LEDs) before turning on the LEDs. Once flushed, the desired flow
rate was set on the syringe pump and the LEDs were turned on after taking an initial sample of
the reaction mixture. The reactor outlet stream was sampled once the desired residence time was
7 cm
achieved, allowing a few extra minutes to ensure the steady-state composition was being
measured. Samples were analyzed by HPLC and the conversion of the starting material at each
time point is reported in Table S1.
CFL
To a 40 mL vial with a 1 cm cross stir bar was added solid Catalyst 1 (1.12 mg, 1 mol,
0.001 equiv.), 100 mg biphenyl (internal standard). This was dissolved in 4.1 mL toluene (note:
dissolution required sonication for 30 minutes at 40 °C). Once completely dissolved 2-methyl-2-
(vinyloxy)propane (0.584 mL, 4.99 mmol, 5 equiv.) was added by calibrated pipet followed by
benzyl piperazine-1-carboxylate (0.194 mL, 0.999 mmol, basis charge). Trip-thiol (0.110 mL,
0.499 mmol, 0.5 equiv.) was also added by calibrated pipet for a total volume of 5 mL. The
solution was allowed to stir with nitrogen sparging at 25 °C for 10 minutes. The nitrogen sparge
was removed, a 0 minute sample was taken and the solution placed 7 cm edge-to-edge from the
previously described CFL. The reaction was left open to air through the course of the reaction.
The temperature was allowed to equilibrate at 25 °C (monitored internally) and the reaction
illuminated by the CFL configured as described above. Time points were taken by removing a 5
μL aliquot and diluting it in 2 mL of acetonitrile while maintaining constant illumination.
Samples were analyzed by HPLC and the conversion of the starting material at each time point is
reported in Table S1.
Reaction Analysis
In all cases, the time point samples were analyzed by HPLC on an Ascentis Express C18
column (15 cm x 4.6 mm x 2.7 μm particle size). Method: 1 mL/min, Solvent A = Water (0.1%
H3PO4 modifier), Solvent B = Acetonitrile (no modifier). Gradient: 0-2 min (10% B), 2-13 min
(10-95% B), 13-13.1 min (95-10% B), 13.1-14 min (10% B). Analysis was performed at 210
nm. Conversion was determined by taking the ratio of starting material to internal standard and
normalizing to the 0 minute time point.
Representative Chromatogram @ 210 nm
Conversion of starting material in the anti-Markovnikov hydroamination for the three
photochemical reactors examined in the main text.
Conversion of starting material (%)
0 0 0.1 0
Figure S4.
Plot of conversion as a function of time for the data in Table S1.
Reaction Notes:
This product was not reported in the literature and characterization spectra can be found at
the end of the Supporting Materials. The reaction components were chosen to provide a UV-Vis
handle for the reaction. Reaction materials were obtained from commercial sources and used as
described without purification. In one instance, the reaction was carried out to 96% conversion
which required 70 minutes of irradiation with the laser.
The Anti-Marknovnikov Hydroacetoxylation Comparison(2, 3)
Laser
To a 40 mL vial with a 1 cm cross stir bar was added benzoic acid (0.363 g, 2.97 mmol, 4
equiv.) and dissolved by 3.2 mL DCE added via serological pipet. Lutidine (0.021 mL, 0.186
mmol, 0.25 equiv.), trans-anethole (0.121 mL, 0.742 mmol, basis charge) and thiophenol (0.066
mL, 0.594 mmol, 0.8 equiv.) were sequentially added via calibrated pipet. A standard solution
of 9-mesityl-10-methylacridinium tetrafluoroborate (Catalyst 2) had been prepared at 0.000167
M and 1.33 mL of this solution was added to the vial by calibrated pipet. The reaction mixture
was sonicated until homogeneous. The reaction was then equilibrated at 25 °C on a stir plate and
a 0 minute sample was taken. The reaction was then illuminated by laser as described above.
Time points were taken by turning off the laser, removing a 5 μL aliquot which was diluted into
2 mL of acetonitrile and then re-illuminating the reaction. The reaction was monitored for 60
minutes. At the end of the time course, the internal reaction temperature was recorded at 28.4 °C
and the laser power was measured at 1.58 W. Samples were analyzed by HPLC and the
conversion of the starting material at each time point is reported in Table S2.
LED Flow Reactor
In a clean 100 mL volumetric flask, trans-anethole (2.415 mL, 14.84 mmol, 1 equiv.),
benzoic acid (7.25 g, 59.4 mmol, 4 equiv.), 2,6-lutidine (0.43 mL, 3.71 mmol, 0.25 equiv.),
thiophenol (1.315 mL, 11.88 mmol, 0.8 equiv.), Catalyst 2 (18 mg, 0.045 mmol, 0.003 equiv.),
and a small amount of biphenyl (internal standard) were combined and diluted to the mark in
DCE and dissolved using a sonicator. Two 50 mL syringes were filled with the solution and
secured in the syringe pump. The solution was flushed through the tubing (4.83 mL total
volume, 450 nm LEDs) before turning on the LEDs. Once flushed, the desired flow rate was set
on the syringe pump and the LEDs were turned on after taking an initial sample. The reactor
outlet stream was sampled once the desired residence time was achieved, allowing a few extra
minutes to ensure the steady-state composition was being measured. Samples were analyzed by
HPLC and the conversion of the starting material at each time point is reported in Table S2.
CFL
To a 40 mL vial with a 1 cm cross stir bar was added benzoic acid (0.363 g, 2.97 mmol, 4
equiv.) and dissolved by 3.2 mL DCE added via serological pipet. Lutidine (0.021 mL, 0.186
mmol, 0.25 equiv.), trans-anethole (0.121 mL, 0.742 mmol, basis charge) and thiophenol (0.066
mL, 0.594 mmol, 0.8 equiv.) were sequentially added via calibrated pipet. A standard solution
of Catalyst 2 had been prepared at 0.000167 M and 1.33 mL of this solution was added to the
vial by calibrated pipet. The reaction mixture was sonicated until homogeneous. The reaction
was then equilibrated at 25 °C on a stir plate and a 0 minute sample was taken. Time points were
taken by removing a 5 μL aliquot and diluting it 2 mL of acetonitrile while maintaining constant
illumination. Samples were analyzed by HPLC and the conversion of the starting material at
each time point is reported in Table S2.
Reaction Analysis
photochemical reactors examined in the main text.
* CFL
Figure S5.
Reaction Notes:
The conversion with the CFL light source is misleading as no product was observed under
the reaction conditions only polymerization of the anethole. The anti-Markovnikov selectivity
was verified by independent synthesis of the possible isomers.
The Pyrazole Synthesis Comparison(4) Laser
To a 40 mL vial with a 1 cm cross stir bar was added 2-benzylidenemalononitrile (0.077 g,
0.499 mmol, basis charge), which was dissolved in 4.62 mL of acetonitrile. To this solution was
Benzoic
Acid
t
Thiophenol
added 0.187 mL of a 0.00133 M solution of Ru(bpy)3Cl23H2O (Catalyst 3) in acetonitrile.
Methylhydrazine (0.025 mL, 0.549 mmol, 1.1 equiv.) was then added via calibrated pipet. The
reaction was then stirred for 10 minutes at 25 °C. A 0 minute time point was taken and the
reaction illuminated as described above. Time points were taken by turning off the laser,
removing a 5 μL aliquot which was diluted into 2 mL of acetonitrile, and then re-illuminating the
reaction. The reaction was monitored for 60 minutes. At the end of the time course, the internal
reaction temperature was recorded at 25 °C and the laser power was measured at 1.70 W.
LED Flow Reactor
In a clean 50 mL volumetric flask, 2-benzylidenemalononitrile (1.542 g, 10 mmol, 1
equiv.), methylhydrazine (0.579 mL, 11 mmol, 1.1 equiv.), and a small amount of biphenyl
(internal standard) were combined and diluted to the mark in acetonitrile. This solution was
charged to a 50 mL syringe and secured in the syringe pump. In a separate 50 mL volumetric
flask, Catalyst 3 (3.74 mg, 5 μmol, 0.0005 equiv.) was added and diluted to the mark in
acetonitrile. This solution was charged to a separate syringe and secured in the same syringe
pump. The two solutions were flushed through the Y-mixer and tubing (4.83 mL total volume,
450 nm LEDs) before turning on the LEDs. Once flushed, the desired flow rate was set on the
syringe pump and the LEDs were turned on after taking an initial sample. The reactor outlet
stream was sampled once the desired residence time was achieved, allowing a few extra minutes
to ensure the steady-state composition was being measured. Samples were analyzed by HPLC
and the conversion of the starting material at each time point is reported in Table S3.
CFL
To a 40 mL vial with a 1 cm cross stir bar was added 2-benzylidenemalononitrile (0.077 g,
0.499 mmol, basis charge) which was dissolved in 4.62 mL of acetonitrile. To this solution was
added 0.187 mL of a 0.00133 M solution of Catalyst 3 in acetonitrile. Methylhydrazine (0.025
mL, 0.549 mmol, 1.1 equiv.) was then added via calibrated pipet. The reaction was then stirred
for 10 minutes at 25 °C. A 0 minute time point was taken and the reaction illuminated as
described above. Time points were taken by removing a 5 μL aliquot which was diluted into 2
mL of acetonitrile while constant illumination of the reaction mixture was maintained. Samples
were analyzed by HPLC and the conversion of the starting material at each time point is reported
in Table S3.
Reaction Analysis
Table S3.
Conversion of starting material in the pyrazole synthesis for the three photochemical reactors
examined in the main text.
0 0 0 0
Figure S6.
Reaction Notes:
Prior to illumination the malonate reacts completely to give the reaction intermediate with a
retention time of 4.49 minutes as shown in the chromatogram above. Conversion is based on the
disappearance of this intermediate.
The Trifluoromethylation Comaparison(5) Laser
To a 40 mL vial with a 1 cm cross stir bar was added 1,4-dimethoxybenzene (0.175 g, 1.26
mmol, basis charge) and pyridine N-oxide (0.361 g, 3.80 mmol, 3 equiv.). To this was added
Catalyst 3 (0.47 mg, 0.63 μmol, 0.0005 equiv.) The solids were dissolved in 4.3 mL of propylene
carbonate. 150 μL of trifluorotoluene was then added as internal standard. Once the solids
dissolved, the reaction was placed in an aluminum block in and submerged in an ice bath. The
reaction was stirred in the ice bath for 5 minutes until it was equilibrated at 1 °C. To this stirring
solution trifluoroacetic anhydride (0.555 mL, 3.93 mmol, 3.1 equiv.) was added dropwise by
calibrated pipet such that the temperature never exceeded 5 °C. Once the addition was complete,
the 0 minute time point was taken and the reaction placed below the 450 nm laser. The reaction
was illuminated as described above. For each sample, the laser was turned off, a 5 μL aliquot
was taken and diluted into 2 mL of acetonitrile, and the reaction was illuminated again. After 7
minutes, a precipitate began to form in the reaction and after 11 minutes the reaction was very
cloudy. The reaction was monitored for 15 minutes. At the end of the time course, the internal
reaction temperature was recorded at 6 °C and the laser power was measured at 1.67 W.
LED Flow Reactor
In a clean 50 mL volumetric flask, 1,4-dimethoxybenzene (3.45 g, 25 mmol, 1 equiv.),
pyridine N-oxide (7.13 g, 75 mmol, 3 equiv.), Catalyst 3 (9.36 mg, 13 μmol, 0.0005 equiv.), and
a small amount of trifluorotoluene (internal standard) were combined and diluted to the mark in
propylene carbonate. This solution was charged to a 50 mL syringe and secured in the syringe
pump. In a separate 50 mL volumetric flask, trifluoroacetic anhydride (10.95 mL, 78 μmol, 3.1
equiv.) was added and diluted to the mark in propylene carbonate. This solution was charged to
a separate syringe and secured in the same syringe pump. The two solutions were flushed
through the Y-mixer and tubing (4.83 mL total volume, 450 nm LEDs) before turning on the
LEDs. The cooling bath was set to 0 °C. Once flushed, the desired flow rate was set on the
syringe pump and the LEDs were turned on after taking an initial sample. The reactor outlet
stream was sampled once the desired residence time was achieved, allowing a few extra minutes
to ensure the steady-state composition was being measured. Samples were analyzed by HPLC
and the conversion of the starting material at each time point is reported in Table S4.
CFL
To a 40 mL vial with a 1 cm cross stir bar was added 1,4-dimethoxybenzene (0.175 g, 1.26
mmol, basis charge) and pyridine N-oxide (0.361 g, 3.80 mmol, 3 equiv.). To this was added
Catalyst 3 (0.47 mg, 0.63 μmol, 0.0005 equiv.). The solids were dissolved in 4.3 mL of
propylene carbonate. Once the solids dissolved, the reaction was placed on a cold plate to avoid
obscuring the light. The reaction temperature was monitored by internal thermocouple. To this
cooled solution trifluoroacetic anhydride (0.555 mL, 3.93 mmol, 3.1 equiv.) was added dropwise
by calibrated pipet such that the temperature never exceeded 5 °C. Once the addition was
complete, the 0 minute time point was taken and the reaction placed below the 450 nm laser.
The reaction was illuminated as described above. Samples were taken with constant illumination
of the reaction. Samples consisted of a 5 μL aliquot diluted into 2 mL of acetonitrile. Samples
were analyzed by HPLC and the conversion of the starting material at each time point is reported
in Table S4.
Reaction Analysis
* CFL
Figure S7.
Internal
Standard
Reaction Notes:
Batch variation in the pyridine N-oxide gave variations in rate and byproduct formation for
this reaction. Some batches from commercial sources were completely ineffective in the
reaction. Propylene carbonate was used rather than the reported acetonitrile in an effort to keep
the reaction solution homogenous to achieve higher conversion. In acetonitrile, a thick slurry
formed at 50% conversion. The product identities were confirmed by purchased standards.
The Aza-Henry Reaction with Eosin Y Comparison(6) All material used in this reaction were obtained with commercial sources except for 2-
phenyl-1,2,3,4-tetrahydroisoquinoline with synthesized according to literature procedures.
Laser
To a 40 mL vial with a 1 cm cross stir bar was added solid 2-phenyl-1,2,3,4-
tetrahydroisoquinoline (0.021 g, 0.1 mmol, basis charge) followed by 100 mg of biphenyl.
Nitromethane (4.5 mL) was added followed by 0.51 mL of a 0.001962 M solution of Eosin Y
(Catalyst 4) (1.00 μmol, 0.01 equiv.). Upon addition of Eosin Y, a bright neon orange color
developed which was attributed to formation of a charge transfer complex. The solution was
allowed to equilibrate at 23 °C for 5 minutes and a 0 minute sample was taken. The reaction was
then illuminated with a 530 nm laser which had been configured exactly the same as the 450 nm
lasers. The reaction was sampled periodically by turning off the laser and taking a 5 μL aliquot
and diluting that into 2 mL of acetonitrile. The reaction was monitored for 20 minutes. At the
end of the time course, the internal reaction temperature was recorded at 27.4 °C and the laser
power was measured at 1.65 W. Samples were analyzed by HPLC and the conversion of the
starting material at each time point is reported in Table S5.
LED Flow Reactor
In a clean 50 mL volumetric flask, 2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.837 g, 4
mmol, 1 equiv.) and a small amount of biphenyl (internal standard) were combined and diluted
to the mark in nitromethane. This solution was charged to a 50 mL syringe and secured in the
syringe pump. In a separate 50 mL volumetric flask, Eosin Y (Catalyst 4) (26 mg, 40 μmol, 0.01
equiv.) was added and diluted to the mark in nitromethane. This solution was charged to a
separate syringe and secured in the same syringe pump. The two solutions were flushed through
the Y-mixer and tubing (4.75 mL total volume, 525 nm LEDs) before turning on the LEDs. Once
flushed, the desired flow rate was set on the syringe pump and the LEDs were turned on after
taking an initial sample. The reactor outlet stream was sampled once the desired residence time
was achieved, allowing a few extra minutes to ensure the steady-state composition was being
measured. Samples were analyzed by HPLC and the conversion of the starting material at each
time point is reported in Table S5.
CFL
To a 40 mL vial with a 1 cm cross stir bar was added solid 2-phenyl-1,2,3,4-
tetrahydroisoquinoline (0.021 g, 0.1 mmol, basis charge) followed by 100 mg of biphenyl.
Nitromethane (4.5 mL) was added followed by 0.51 mL of a 0.001962 M solution of Eosin Y
(Catalyst 4) (1.00 μmol, 0.01 equiv.). Upon addition of Eosin Y, a bright neon orange color
developed, which was attributed to formation of a charge transfer complex. The solution was
allowed to equilibrate at 23 °C for 5 minutes and a 0 minute sample was taken. The reaction was
then illuminated by the CFL. The reaction was sampled periodically by taking a 5 μL aliquot
and diluting that into 2 mL of acetonitrile while maintaining constant illumination. The reaction
was monitored for 20 minutes. Samples were analyzed by HPLC and the conversion of the
starting material at each time point is reported in Table S5.
Reaction Analysis
Table S5.
Conversion of starting material in the aza-Henry reaction for the three photochemical reactors
0 0 0 0
Figure S8.
Product Internal
Reaction Notes:
Products isolated from the reaction mixture were consistent with reported data. Side by side
comparison of solutions of Eosin Y with and without the substrate demonstrated a shift in the
absorbance profile, although this shift was never quantified. The suggested charge transfer
complex possessed a much higher molar extinction coefficient. To compensate, the reaction was
diluted to a higher degree than reported to allow for increased absorption of light.
C-N Coupling Reaction Order Experiments(7) All materials used in these reactions were purchased from commercial sources and used
without further purification. All stock solutions were prepared and used in these reactions within
24 hours.
Dependence of the Rate of Reaction on the Concentration of DABCO
NiBr23H2O (2.222 mL of a 0.135 M solution in DMAc, 0.3 mmol, 0.05 equiv.), Catalyst 1
(1.293 mL of a 1.16 mM solution in DMAc, 1.5 µmol, 0.00025 equiv.), 1-bromo-4-
(trifluoromethyl)benzene (0.840 mL, 6 mmol, 1 equiv.), pyrrolidine (1.478 mL, 18 mmol, 3
equiv.), and biphenyl as an internal standard were all added to a 20 mL volumetric flask and
diluted to the line with DMAc. The flask was sonicated until the solution was homogeneous.
Three 5 mL aliquots of this solution were pipetted into three separate 40 mL vials, each with its
own magnetic stir bar. Different amounts of DABCO (0.210 g, 1.875 mmol, 1.25 equiv., 0.375
M; 0.252 g, 2.250 mmol, 1.5 equiv., 0.45 M; 0.337 g, 3.00 mmol, 2 equiv., 0.60 M) were then
added to each vial and sonicated until fully dissolved. For each experiment, the vial was placed
in an aluminum block on a stir plate with the temperature controller set to 50 °C and the
temperature of the vial was allowed to equilibrate prior to starting the reaction. After taking an
initial aliquot for HPLC analysis, the reaction was illuminated as described above. Samples (5
μL) were collected at the desired time points, diluted in 1.5 mL acetonitrile, and analyzed by
HPLC to determine the initial rate of reaction in each experiment. These results are presented in
Table S6 and Figure S9 and show that the initial rate of reaction does not depend on the
concentration of DABCO.
Reaction Analysis
In all cases, the timepoint samples were analyzed by HPLC on an Ascentis Express C18
Table S6.
Concentration of aryl bromide as a function of time with respect to different initial
concentrations of DABCO.
Concentration of aryl bromide (M)
Time (min) 0.375 M DABCO 0.45 M DABCO 0.60 M DABCO
0 0.300 0.300 0.300
1 0.259 0.263 0.253
2 0.217 0.220 0.200
3 0.180 0.181 0.156
5 0.122 0.119 0.095
Figure S9.
Dependence of the initial rates of reaction of aryl bromide on the initial concentration of
DABCO.
Dependence of the Rate of Reaction on the Concentration of Pyrrolidine
DABCO (1.010 g, 9 mmol, 1.5 equiv.), NiBr23H2O (2.222 mL of a 0.135 M solution in
DMAc, 0.3 mmol, 0.05 equiv.), Catalyst 1 (1.293 mL of a 1.16 mM solution in DMAc, 1.5
µmol, 0.00025 equiv.), 1-bromo-4-(trifluoromethyl)benzene (0.840 mL, 6 mmol, 1 equiv.) and
biphenyl as an internal standard were all added to a 20 mL volumetric flask and diluted to the
line with DMAc. The flask was sonicated until the solution was homogeneous. Three 5 mL
aliquots of this solution were pipetted into three separate 40 mL vials, each with its own
magnetic stir bar. Different amounts of pyrrolidine (0.246 mL, 3 mmol, 2 equiv., 0.6 M; 0.308
mL, 3.75 mmol, 2.5 equiv., 0.75 M; 0.345 mL, 4.2 mmol, 2.8 equiv., 0.84 M) were then added to
each vial. For each experiment, the vial was placed in an aluminum block on a stir plate with the
temperature controller set to 50 °C and the temperature of the vial was allowed to equilibrate
prior to starting the reaction. After taking an initial aliquot for HPLC analysis, the reaction was
y = -0.0357x + 0.294 R² = 0.9917
y = -0.0366x + 0.2973 R² = 0.9954
y = -0.0414x + 0.2922 R² = 0.9852
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.375 M DABCO
0.45 M DABCO
0.6 M DABCO
illuminated as described above. Samples (5 μL) were collected at the desired time points, diluted
in 1.5 mL acetonitrile, and analyzed by HPLC to determine the initial rate of reaction in each
experiment. These results are presented in Table S7 and Figure S10 and show that the initial rate
of reaction does not depend on the concentration of pyrrolidine.
Table S7.
concentrations of pyrrolidine.
Time (min) 0.60 M pyrrolidine 0.75 M pyrrolidine 0.84 M pyrrolidine
0 0.300 0.300 0.300
1 0.270 0.261 0.260
2 0.227 0.223 0.214
3 0.192 0.184 0.172
4 0.162 0.153 0.140
5 0.143 0.128 0.113
Figure S10.
pyrrolidine.
Dependence of the Rate of Reaction on the Concentration of Ni
DABCO (1.010 g, 9 mmol, 1.5 equiv.), Catalyst 1 (1.293 mL of a 1.16 mM solution in
DMAc, 1.5 µmol, 0.00025 equiv.), 1-bromo-4-(trifluoromethyl)benzene (0.840 mL, 6 mmol, 1
eq.), pyrrolidine (1.478 mL, 18 mmol, 3 equiv.), and biphenyl as an internal standard were all
added to a 20 mL volumetric flask and diluted to the line with DMAc. The flask was sonicated
until the solution was homogeneous. Three 5 mL aliquots of this solution were pipetted into
y = -0.0327x + 0.2973 R² = 0.989
y = -0.0349x + 0.2956 R² = 0.994
y = -0.0382x + 0.2954 R² = 0.9921
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.6 M Pyrrolidine
0.75 M Pyrrolidine
0.84 M Pyrrolidine
three separate 40 mL vials, each with its own magnetic stir bar. Different amounts of a 0.135 M
solution of NiBr23H2O in DMAc (0.056 mL, 7.5 µmol, 0.005 equiv., 1.5 mM; 0.111 mL, 15
µmol, 0.01 equiv., 3.0 mM; 0.222 mL, 30 µmol, 0.02 equiv., 6.0 mM) were then added to each
vial. For each experiment, the vial was placed in an aluminum block on a stir plate with the
temperature controller set to 50 °C and the temperature of the vial was allowed to equilibrate
prior to starting the reaction. After taking an initial aliquot for HPLC analysis, the reaction was
illuminated as described above. Samples (5 μL) were collected at the desired time points, diluted
in 1.5 mL acetonitrile, and analyzed by HPLC to determine the initial rate of reaction in each
experiment. These results are presented in Table S8 and Figure S11 and show that the initial rate
of reaction depends on the concentration of Ni catalyst, as mentioned in the main text.
Table S8.
concentrations of Ni.
Time (min) 1.5 mm Ni 3.0 mM Ni 6.0 mM Ni
0 0.300 0.300 0.300
1 0.299 0.279 0.269
2 0.293 0.261 0.229
3 0.290 0.235 0.192
4 0.285 0.224 0.161
5 0.280 0.207 0.135
Figure S11.
Dependence of the initial rates of reaction of aryl bromide on the initial concentration of Ni.
Dependence of the Rate of Reaction on the Concentration of Aryl Bromide
y = -0.0041x + 0.3017 R² = 0.9724
y = -0.0188x + 0.2981 R² = 0.991
y = -0.0339x + 0.2989 R² = 0.996
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.5 mol % Ni (1.5 mM)
1 mol % Ni (3.0 mM)
2 mol % Ni (6.0 mM)
To three separate 40 mL vials containing magnetic stir bars, DABCO (0.252 g, 2.25 mmol),
Catalyst 1 (0.323 mL of a 1.16 mM solution in DMAc, 0.375 µmol), NiBr23H2O (0.556 mL of a
0.135 M solution in DMAc, 0.075 mmol), pyrrolidine (0.370 mL, 4.5 mmol), and biphenyl as an
internal standard were all added and sonicated until each solution was homogeneous. Different
amounts of 1-bromo-4-(trifluoromethyl)benzene (0.140 mL, 1 mmol, 0.2 M; 0.280 mL, 2 mmol,
0.4 M; 0.560 mL, 4 mmol, 0.8 M) were then added to each vial, along with neat DMAc (3.611
mL, 3.471 mL, and, 3.191 mL, respectively) to bring the total volume in each vial to 5 mL. For
each experiment, the vial was placed in an aluminum block on a stir plate with the temperature
controller set to 50 °C and the temperature of the vial was allowed to equilibrate prior to starting
the reaction. After taking an initial aliquot for HPLC analysis, the reaction was illuminated as
described above. Samples (5 μL) were collected at the desired time points, diluted in 1.5 mL
acetonitrile, and analyzed by HPLC to determine the initial rate of reaction in each experiment.
These results are presented in Table S9 and Figure S12 and show that the initial rate of reaction
depends on the concentration of the aryl bromide, as mentioned in the main text.
Table S9.
concentrations of aryl bromide.
Time (min) 0.2 M aryl bromide 0.4 M aryl bromide 0.8 M aryl bromide
0 0.200 0.400 0.800
1 0.157 0.356 0.765
2 0.118 0.300 0.703
3 0.082 0.252 0.626
4 0.058 0.218 0.584
5 0.039 0.187 0.544
Figure S12.
aryl bromide.
25 W Laser System General Details System Specifications
The 450 nm 25 Watt laser system was purchased from Coherent (Model #100404809). The
system was powered by a Delta Elektronika SM330-AR-22 Power Supply. The laser system and
power supply were design to run at 110 Volts with variable current to allow control of the output
power. The laser is fiber coupled via SMA connection with a 400/480 μm core fiber. Emission
spectrum and calibration data are available from Coherent.
Laser Optics
The beam expanders used in this report were custom built from parts commercially
available from Thor Labs. As a safety precaution, each time the fiber core was switched between
different beam expanders, the fiber was inspected with a Fiber Scope to minimize the risk of
burn-in. The variations of the optics were designed according to the following diagrams (Figure
S13) which allowed easy adjustability of the beam diameter. Power distribution was Gaussian
by necessity as commercially available “Top-Hat” diffusers rated to these power levels were not
readily available. Beam diameter was adjusted depending on the type of beam expander used
either Type I or Type II.
y = -0.0325x + 0.1904 R² = 0.9793
y = -0.0436x + 0.3945 R² = 0.9895
y = -0.0543x + 0.806 R² = 0.9876
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Figure S13.
Schematic diagram of the Type I and Type II beam expanders.
Catalyst Concentration Rate Experiments
All materials used in this reaction were purchased from commercial sources and used
without further purification. To minimize experimental error across the series of reactions, a
single reaction solution without catalyst was prepared. Catalyst was then added to equal volume
aliquots of this solution. At low catalyst concentration, the catalyst was added by way of a
standard solution described below. At high concentrations, solid catalyst was weighed and
added to the reaction mixture directly. At both high and low catalyst concentration, the volume
of catalyst added as a solid or in solution was negligible (>1.0% of the total volume) and was
ignored in the analysis. The reaction vessel was a 250 mL jacketed beaker purchased from
Chemglass (GC-1103-03). The same reactor and stir bar were used for each experiment. The
reactions were all performed over a period of 24 hours where the stability of the prepared
reaction solution was known to 120 hours to give identical results.
Solution Preparation
To a 500 mL media bottle was added NiBr23H2O (18.18 g, 66.7 mmol, 0.05 equiv.) after it
had been pulverized with a mortar and pestle. Next, 500 mL of DMAc was added, the bottle was
sealed, and the solution was stirred overnight at 23 °C with magnetic stirring at 500 rpm. The
next day, in a 2 L media bottle was added solid DABCO (187.30 g, 1667 mmol, 1.25 equiv.). 1-
bromo-4-(trifluoromethyl)benzene (302.1 g, 1333 mmol, basis charge) was then added, followed
by pyrrolidine (287.2 g, 4000 mmol, 3 equiv.). 300 mL of DMAc was added bringing the total
volume up to ~1 L. 5.0 grams of biphenyl was added as internal standard and allowed to
dissolve. The NiBr23H2O solution was then added and the contents stirred for 20 minutes
mechanically. Once complete dissolution had occurred, the solution was transferred to a 2 L
graduated funnel and DMAc was added to a total volume of 1.68 L, reflecting a 0.80 M solution
with respect to aryl bromide. The reaction solution was maintained at ambient temperature and
open to air for the duration of the experiments. The solution was translucent and a deep green
color.
Catalyst Solution
1.4268 g of Catalyst 1 was weighed into a 25.00 mL volumetric flask. DMAc was added up
to the mark, creating a catalyst solution of 0.0410 M. The resulting solution was transparent, but
a deep yellow color.
To a clean, dry 250 mL graduated cylinder with a 4 cm egg-shaped Teflon coated stir bar
was added 165 mL of the reaction solution described above. This solution was then poured into
a clean, dry 250 mL jacketed beaker giving a liquid depth of 5 cm. An appropriate amount of
catalyst solution or solid catalyst was charged to the graduated beaker according the following
table:
Amounts of Catalyst 1 in the catalyst concentration rate experiments.
Catalyst Amount Equiv. Mol% Concentration (mM)
0.161 mL Solution 0.00005 0.005 0.04
0.322 mL Solution 0.0001 0.01 0.08
0.805 mL Solution 0.00025 0.025 0.20
1.610 mL Solution 0.0005 0.05 0.40
0.111 g Solid 0.00075 0.075 0.60
0.148 g Solid 0.001 0.1 0.80
0.296 g Solid 0.002 0.2 1.60
0.444 g Solid 0.003 0.3 2.40
0.740 g Solid 0.005 0.5 4.00
The beaker was then connected to a chiller set to 50 °C and the reaction was allowed to
equilibrate to 48 °C internal temperature.
The power supply was set to an output of 1.05 Amps at 110 Volts. Using the Type I beam
expander described in the Laser Optics section, the optics were placed 5.44 cm from the surface
of the reaction solution allowing for complete illumination across the 6.5 cm diameter of the
reactor. Once laser and reactor had been aligned and equilibrated, a 5 μL aliquot and diluted into
2 mL of acetonitrile for the zero point and the reaction illuminated. Time points were taken with
accuracy of ± 1 second while constant illumination was maintained by the laser. Temperature
was recorded in each reaction with the data consistent across the set of reactions. The
temperature equilibrated at 69.0 °C within 1 minute under each set of conditions. At the end of
the time course, the laser power was recorded with a power meter and was consistent at 21.4
Watts at 450 nm. The collected samples were analyzed by HPLC with the ratio of 1-bromo-4-
(trifluoromethyl)benzene to biphenyl normalized to the starting concentration of 0.80 M. The
raw data are given in Table S11.
Table S11.
Concentration of aryl bromide vs. time for the photocatalyst concentration experiments.
0.01
mol%
0.025
mol%
0.05
mol%
0.075
mol%
0.10
mol%
0.50
mol%
0.005
mol%
0.2
mol%
0.3
mol%
(min) 0.08 0.20 0.40 0.60 0.80 4.0 0.04 1.60 2.40
0 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8
1 0.749 0.728 0.721 0.713 0.744 0.782 0.781 0.754 0.768
2 0.650 0.613 0.623 0.622 0.671 0.744 0.731 0.6 0.689
3 0.561 0.512 0.516 0.541 0.563 0.727 0.668 0.619 0.662
4 0.479 0.419 0.451 0.444 0.519 0.704 0.613 0.559 0.634
5 0.406 0.358 0.370 0.403 0.478 0.684 0.559 0.507 0.583
6 0.350 0.297 0.319 0.343 0.432 0.656 0.512 0.472 0.546
8 0.256 0.205 0.235 0.240 0.340 0.619 0.427 0.402 0.492
10 0.185 0.138 0.176 0.189 0.275 0.565 0.360 0.342
Linear regressions were performed from 0-6 minutes (up to 60% conversion in the fastest
reaction as highlighted in Table S11). The data across this region were strongly linear, giving
correlation coefficients (R 2 ) of >0.98. The absolute values of these slopes from these
regressions are tabulated in Table S12 and used to construct the graphs in Figure 2.
Table S12.
Loading
(mol%)
Catalyst Concentration
(mM) Rate (M/min) ln(rate) 0.01 0.08 0.0788 0.025 0.2 0.0872 -2.43955 0.05 0.4 0.0827 -2.49254 0.075 0.6 0.0775 -2.55748 0.1 0.8 0.0638 -2.752 0.5 4 0.0238 -3.73807
0.005 0.05 0.0509 0.02 1.6 0.0573 -2.85945 0.03 2.4 0.0424 -3.16061
Solution Depth Rate Experiments All materials used in this reaction were purchased from commercial sources and used
without further purification. To minimize experimental error across the series of reactions, a
single reaction solution catalyst was prepared and used within 24 hours.
Reaction Solution Preparation To a 500 mL media bottle was added NiBr23H2O (18.18 g, 66.7 mmol, 0.05 equiv.) after it
had been pulverized with a mortar and pestle. Next, 500 mL of DMAc was added, the bottle was
sealed, and the solution was stirred overnight at 21 °C with magnetic stirring at 500 rpm. The
next day, in a 2 L media bottle was added solid DABCO (187.30 g, 1667 mmol, 1.25 equiv.) and
Catalyst 1 (0.374 g, 0.333 mmol, 0.00025 equiv.). 1-bromo-4-(trifluoromethyl)benzene (302.1 g,
1333 mmol, basis charge) was then added, followed by pyrrolidine (287.2 g, 4000 mmol, 3
equiv.). 300 mL of DMAc was added bringing the total volume up to ~1 L. 10.8 grams of
biphenyl was added as internal standard and allowed to dissolve. The NiBr23H2O solution was
then added and the contents stirred for 60 minutes mechanically. Once complete dissolution had
occurred, the solution was transferred to a 2 L graduated funnel and DMAc was added to a total
volume of 1.68 L, reflecting a 0.80 M solution with respect to aryl bromide. The reaction was
solution was maintained at ambient temperature and open to air for the duration of the
experiments. The solution was translucent and a deep green color.
Experiment
To a dry, clean 250 mL graduated cylinder was added the previously prepared solution.
The amount of solution charged was varied according to the Table SXX1. After measuring the
solution, it was transferred to a clean, dry 250 mL jacketed beaker with a 4 cm egg-shaped
Teflon coated stir bar. The beaker was then equilibrated to 49 °C internal temperature via a
chiller set to 50 °C.
The laser power supply was preset to provide 1.05 Amps at 110 Volts. A Type I beam
expander was used as described in the Laser Optics section of this report. The bottom lens of the
beam expander was adjusted to be 5.44 cm from the surface of the reaction solution allowing for
complete illumination across the 6.5 cm diameter of the reactor. The 5.44 cm distance between
the solution surface and optics was maintained as the absolute height of the solution was
increased.
Once the laser and reactor had been aligned and equilibrated, a 5 μL aliquot was taken and
diluted into 2 mL of acetonitrile for the zero point and the reaction illuminated. Time points
were taken with accuracy of ± 1 second while constant illumination was maintained by the laser.
Temperature was recorded in each reaction and, as expected, varied with each volume as shown
in Table S13.
Table S13.
Volume, liquid depth, and temperature data in the solution depth rate experiments.
Volume of Reaction Solution
Jacketed Beaker (cm)
66 2 72.7
99 3 70.6
132 4 70.1
165 5 69.1
198 6 67.3
231 7 66.3
262 8 66.7
At lower volumes, the reaction was anticipated to proceed at an enhanced rate, so additional
early time points were taken to provide adequate data for linear regression analysis. At the end
of the time course, the laser power was measured with a power meter at 21.4 Watts. The
collected samples were analyzed by HPLC with the ratio of 1-bromo-4-(trifluoromethyl)benzene
to biphenyl normalized to the starting concentration of 0.80 M. The data is shown in Table S14.
Table S14.
Concentration of aryl bromide vs. time for the solution depth rate experiments.
Depth of the Solution (cm)
Time (min) 2 3 4 5 6 7 8
0 0.8 0.8 0.8 0.8 0.8 0.8 0.8
0.5 0.679 0.730 -- -- -- -- --
1.5 0.376 0.538 -- -- -- -- --
2.5 0.184 0.362 -- -- -- -- --
4 0.058 0.170 0.270 0.336 0.412 0.481 0.501
5 0.025 0.104 0.198 0.255 0.338 0.425 0.420
6 0.006 0.066 0.140 0.205 0.278 0.364 0.375
8 0 0.034 0.072 0.127 0.191 0.297 0.298
10 -- -- 0.033 0.074 0.126 0.234 0.232
In the table, the shaded cells represent the data used in the linear regression. In each
regression, the correlation coefficients were

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