Photochemistry with laser radiation in condensed phase using miniaturized photoreactors

Article abstract of DOI:10.3762/bjoc.8.135

Miniaturized microreactors enable photochemistry with laser irradiation in flow mode to convert azidobiphenyl into carbazole with high efficiency.

Full text of DOI:10.3762/bjoc.8.135

Photochemistry with laser radiation in condensed
phase using miniaturized photoreactors
Elke Bremus-Köbberling1, Arnold Gillner1, Frank Avemaria2, Céline Réthoré2
and Stefan Bräse*2,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1213–1218.
1Fraunhofer Institute for Laser Technology, Steinbachstrasse 15,
D-52074 Aachen, Germany, 2Institute of Organic Chemistry,
Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, D-76131
Karlsruhe, Germany and 3Institute of Toxicology and Genetics,
Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1,
D-76344 Eggenstein-Leopoldshafen, Germany
doi:10.3762/bjoc.8.135
Received: 31 March 2012
Accepted: 18 June 2012
Published: 31 July 2012
This article is part of the Thematic Series "Recent developments in
chemical diversity".
Email:
Stefan Bräse* - braese@kit.edu
Guest Editor: J. A. Porco Jr.
* Corresponding author
© 2012 Bremus-Köbberling et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
azides; chemical diversity; flow chemistry; heterocycles; laser; micro
reactor
Abstract
Miniaturized microreactors enable photochemistry with laser irradiation in flow mode to convert azidobiphenyl into carbazole with
high efficiency.
Introduction
Classical combinatorial chemistry [1,2] approaches usually aim Photochemical processes are in this case particularly interesting
at the synthesis of multi-milligram amounts of new compounds because of their enhanced molecular activation [8]. Photochem-
to extend screening decks used in multiple screening campaigns istry in microreactors is an emerging research area [9], and
[3]. An alternative method enabled by the maturing microreac- especially photocatalytic reactions have been investigated in
tion technology and the use of flow chemistry [4-6] is the inte- detail by Matsushita et al. [10,11]. To date there are a couple of
gration of synthesis and screening in one integrated lab-on-a- reported examples combining miniaturized reaction systems
chip approach [7].
with synthetic laser photochemistry [5,6,9,12-28].
Using this methodology we have integrated photochemistry in a The influence of photons, which are delivered via a suitable
miniaturized reaction setup to enable combinatorial flow chem- light-transparent window, on the processes running in miniatur-
istry in lab-on-a-chip applications.
ized photoreactors, is investigated with a focus on increasing
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the yield and selectivity as well as decreasing the reaction time. increasing depth, and different connections for the reagent
Photochemistry with laser radiation is a promising tool to entrance (Figure 1).
broaden the application spectrum of miniaturized systems, by
facilitating a powerful activation step due to a wide range of
available wavelengths and energy ranges [29,30]. Moreover, the
optical systems can be designed in a way that the reaction initia-
tion by photons and an additional online analysis of the running
reaction is feasible.
Results and Discussion
Design and fabrication
In order to realize photochemical synthesis, several reactors and
small reactor arrays with reaction volumes of approximately
1 mL down to 35 µL were developed. These reactors were espe-
cially designed for the stimulation of photochemical reactions
(UV–vis radiation) as well as for demanding reaction condi-
tions, such as the rapid elevation of temperature (with pulsed
IR-laser radiation) or pressure pulses (due to the evaporation of
the solvent upon the introduction of energy).
Several microstructured reactor types were designed and
produced for reactions in the liquid phase. They are equipped
with quartz-glass cover plates, transparent to the laser radiation,
pressed onto an appropriate sealing material. Moreover, chan-
nels suitable for the mixing and reaction of two or more
isopycnic solutions were built in a polymer bloc by mechanical
treatment [31]. The provision of bubble-free fluid is ensured in
this case by microchannels in at least two levels, which are built
from corresponding structured layers. These reactors were made
of polyether ether ketone (PEEK) and polytetrafluoroethylene
(PTFE) [32] to study the influence of side reactions with the
reactor material, which could reduce the yield of the desired
Figure 1: Four-fold PEEK-reactors with increasing chamber depths
from left to right and different techniques of fluid connection; top: glued
PEEK-capillaries, bottom: ¼ in. screw connections.
reaction product. The multilayer system is placed in a stainless- Photochemistry
steel frame. The combinatorial synthesis of heterocycles and among them of
carbazole is of particular interest since they are potential active
With this type of reactor, it is possible to realize a series of reac- pharmaceutical compounds [33-35]. The photolysis of 2-azido-
tions in parallel by arranging the reactor chambers in an (n × m) biphenyl (1) with the help of a conventional UV-lamp has been
matrix. The microreactors applied for this study have four reac- used for the synthesis of carbazole (2) since 1960 (Scheme 1)
tion chambers with varying volumes of the chambers due to [36-39].
Scheme 1: Synthesis of carbazole (2) by photolysis.
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Beilstein J. Org. Chem. 2012, 8, 1213–1218.
However, there are only a few examples of substituted products Frequency-tripled Nd:YAG laser radiation (λ = 355 nm, 8 kHz
obtained by this reaction, and several side-products, such as the pulse frequency; pulse duration 26 ns) was chosen because the
corresponding azo-derivatives, are usually formed [36,40-44]. wavelength is close to that of the applied UV-lamp, 355 nm is
During the past few years, we successfully employed triazene usually within the absorption area of azides, and this laser type
resins, such as 4, which are readily available from aniline in the is commonly used in most laser labs. We applied a single-pulse
synthesis of a library of aromatic derivatives [45-48]. Moreover, power of 0.16 to 3 W resulting in pulse energies between 4
triazene-resins are perfectly suitable for the synthesis of and 87 nJ and energy densities of approximately 0.02 to
arylazides 5 (Scheme 2) [49].
0.17 µJ/cm2 within a defocused laser spot of 0.2 to 0.5 cm2, to
carry out the same reaction (Scheme 1), but carbazole was
obtained much faster from 2-azidobiphenyl (1). Compared to
conventional UV sources, the use of laser irradiation clearly
accelerated the reaction: from 18 h (Xe lamp, Figure 2) to 30 s
(Nd:YAG laser) for 50% yield and 95% selectivity, calculated
from the data presented in Figure 3. This reaction was success-
fully carried out in a miniaturized photoreactor (Figures 3–6).
The monomolecular reaction can be realized by using laser radi-
ation of 355 nm wavelength as a photon source, in a clean way,
avoiding almost completely the formation of the undesired
Scheme 2: Synthesis of arylazides 2 by solid-phase synthesis.
The photochemical decomposition of arylazides into carbazoles
is appropriate for application in miniaturized photoreactors,
since significant results can be observed by an online analysis
through HPLC and GC [50]. Because of the miniaturization,
online analysis is especially suitable for our setup.
We therefore investigated whether the photoreaction can be
realized in miniaturized photoreactors and to what extent the
use of a laser as a photon source is advantageous. The irradi-
ation of 2-azidobiphenyl (1) in methanol with a conventional
xenon lamp (400 W, λ > 345 nm) required 18 h for 50% yield
(95% selectivity) in a 10 mm cell with an 8 mm light-exposure
diameter (Figure 2).
Figure 3: Carbazole synthesis in miniaturized photoreactors Type II
(PEEK and Teflon), flow control, P = 0.92 W.
Figure 2: Photolysis results in batch setup (flask) with a xenon lamp
(400 W, λ > 345 nm).
Figure 4: Carbazole synthesis in miniaturized photoreactors Type II
(PEEK and Teflon), power control, flow 26 mL/h.
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Beilstein J. Org. Chem. 2012, 8, 1213–1218.
The deviations from linearity in the low power area of Figure 4
can be attributed to fluctuations of the laser power. For the
high-power area, a correlation between yield, power and reac-
tion time, which can be explained by kinetics, is observed.
Conclusion
The preparation and application of polymeric, miniaturized
photoreactors, equipped for the effective use of photons in the
reaction chamber, provided by frequency-converted laser
sources, was successfully shown.
With these reactors or reactor components, the photonic influ-
ence on reactions in miniaturized photoreactors was proven to
be useful in parameter studies in which laser power and flow
rate were varied.
Figure 5: Test setup with continuously operating, miniaturized
photoreactor.
The advantages of laser chemistry in the condensed phase
compared to standard photochemical approaches have been
shown in this preliminary study, proving the suitability of laser
photochemistry for organic synthesis. Thanks to the further
miniaturization and the availability of new moderately priced
laser systems even better suited beam sources can be provided
for photochemistry.
In the described experiments, laser radiation of 355 nm wave-
length (frequency-tripled Nd:YAG) was used. Since the spec-
tral range of interest for most photoreactions ranges from the
ultraviolet to the visible region, tunable laser systems (optical
parametric oscillators) feature promising properties for use
photochemical experiments. Thus, the irradiation wavelength
can be adapted to the needs of the reaction (e.g., to a shifted
absorption maximum of the reactant due to substitution) facili-
tating a large range of applications of this technique. Further-
more, IR laser sources (diode laser, Nd:YAG laser, CO2 laser)
Figure 6: The miniaturized photoreactor (PEEK) during photolysis.
diazo derivatives 3. The side reaction is supposedly reduced due could be applied for pulsed temperature and pressure elevation
to a lesser effect of heating owing to the small bandwidth irradi- in microreactors, as well as microwave stimulation to accel-
ation and minimized exposure time through the miniaturized erate reactions.
flow setup.
Experimental
During these tests, it was shown that a largely better selectivity All starting materials and products were characterized by stan-
can be achieved, compared to the one obtained in a standard UV dard techniques (1H NMR, 13C NMR, and elemental analysis)
irradiation setup (Figure 2). Experiments were performed in and are compared with authentic samples. The products were
batch as well as flow-injection configuration. The continuous analyzed by GC–MS (internal standard, dodecane) and/or
process used allowed us to vary the residence time in the reactor HPLC.
by regulating the flow speed of the reactant solution, with the
help of a syringe pump (Figure 5).
A solution of 2-azidobiphenyl (1) was continuously added to a
miniaturized reactor of type II (see Figure 1, dimension of the
For this study, reactors made of PEEK, as well as PTFE reac- reactor chamber 3 × 5 mm, 35 μL volume) with a syringe pump.
tors were used, leading to similar yields of carbazole (Figure 3 The chamber was continuously irradiated with a Nd:YAG laser
and Figure 4), showing no major influence of the reactor ma- (355 nm). At a constant flow of 26 mL/h, the laser-pulse power
terial on the reaction.
was varied from 0.16 to 1.28 W. Furthermore, at a constant
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Beilstein J. Org. Chem. 2012, 8, 1213–1218.
16.For a commercial photo-microreactor see:
intermediate power of 0.92 W the flow rate (10 to 100 mL/h)
and therefore the dwell time (exposure time) in the reactor was
varied. The yield was determined by HPLC.
http://www.ymc-europe.com/ymceurope/products/flow-chemistry/flow-c
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Supporting Information File 1
Description of the flow reactor setup, kinetics, experimental
procedures and spectroscopic data of all compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-135-S1.pdf]
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We thank the Fonds der Chemischen Industrie for financial
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