A microfabricated nanoreactor for safe, continuous generation and use of singlet oxygen

Article abstract of DOI:10.1021/op0155155

Singlet oxygen was effectively and safely generated in a nanoscale reactor and used for the synthesis of ascaridole. The technique allows for the generation of singlet oxygen without the inherent dangers of large quantities of oxygenated solvents. The methodology allows for facile scale-out of the process.

Full text of DOI:10.1021/op0155155

Organic Process Research & Development 2002, 6, 187−189
A Microfabricated Nanoreactor for Safe, Continuous Generation and Use of
Singlet Oxygen
Robert C. R. Wootton, Robin Fortt, and Andrew J. de Mello*
AstraZeneca/SmithKline Beecham Centre for Analytical Sciences, Imperial College of Science, Technology and Medicine,
Department of Chemistry, Exhibition Road, South Kensington, London, SW7 2AY, U.K.
Scheme 1. Singlet oxygen addition to r-terpinene
Abstract:
Singlet oxygen was effectively and safely generated in a
nanoscale reactor and used for the synthesis of ascaridole. The
technique allows for the generation of singlet oxygen without
the inherent dangers of large quantities of oxygenated solvents.
The methodology allows for facile scale-out of the process.
interest to the chemical community.6 The term “nanoreactor”
denotes reactors with an instantaneous reaction volume most
conveniently measured in nanolitres. Because of increased
efficiencies of mixing and separation combined with high
rates of thermal and mass transfer, nanoreactors are ideal
for processing valuable or hazardous reaction components
and in many instances for improving reaction selectivities.7
Moreover, the low-Reynolds-number environments encoun-
tered within most nanofluidic devices afford a high degree
of control over processes performed in continuous-flow
formats.7 Importantly, continuous-flow alternatives to tradi-
tional batch processes can be scaled with facility by the use
of a multiparallel (or scale-out) approach.6
Motivated by these advantages, we describe herein the
application of nanoreactor technology to the safe, efficient,
continuous-flow synthesis of ascaridole from R-terpinene,
as shown in Scheme 1. Miniaturising the reactor footprint
takes advantage of the small length scales and high surface-
to-volume ratios of microfabricated devices, and since the
microfluidic channels fabricated are approximately 50 µm
deep, radiation can easily penetrate through the entirety of
the reaction environment. Importantly, the technique allows
for the generation of singlet oxygen without the inherent
dangers of large quantities of oxygenated solvents.
Introduction
The use of photosensitisers to effect the singlet oxygen
oxidation of terpenes and conjugated dienes has a long
history, particularly in the perfume industry.1 Despite the
utility of the functionality introduced by this transformation
there are inherent difficulties in adapting the process for
large-scale production. These include the difficulty of
introducing adequate intensities of the required wavelength
of light into the reactor and achieving sufficient oxygen
saturation. The challenge for the process chemist in achieving
adequate illumination is made more difficult by the strong
absorption of sensitiser dyes. This leads to a shortened
effective path length even under quite powerful irradiation
and also the formation of dimers and higher aggregates, many
of which are insoluble.2 Furthermore, the use of tungsten
lamps or sunlight in this regard brings with it difficulties
for scale-up and unwanted sample heating, necessitating the
use of collimators or refrigeration. The explosive nature of
oxygenated organic liquids3 is well-known and can lead to
significant health and safety issues.4 Even aerated organic
solvents can be extraordinarily hazardous on a laboratory
scale and more so on an industrial scale. Recent develop-
ments in this area have addressed the problem of adequate
illumination but still leave the safety issues associated with
large quantities of oxygenated organic solvents unsolved. For
example, most “small tube” flow devices involve recirculat-
ing feedstock from a large reservoir through an illuminated
tube, leaving large quantities of aerated solvents in reservoir.5
Yields for this type of synthesis are as high as 90% for
terpene oxidation, but the problems posed by accidental pipe
rupture are still of concern.
Nanoreactor Fabrication
The glass microchip (footprint 5 cm × 2 cm) was made
in-house using direct-write laser lithography, wet chemical
etching and bonding techniques as previously described.8
Briefly, a positive photoresist (S 1818, Shipley Corporation,
Whitehall, PA) was spun onto the surface of a glass substrate,
and the channel design transferred to the substrate into the
photoresist using a DWL system (DWL2.0, Heidelberg
Instruments, Heidelberg, Germany). After the photoresist was
developed (Microposit 351, Shipley Europe Ltd, Coventry,
UK), the channels were etched into the glass substrate using
a buffered oxide etching solution (HF/NH4F). A glass cover
The application of nanoreactor technology to address
difficulties in synthetic chemistry is an area of increasing
* Author for correspondence. Fax: +44 (0)207 594 5833. Telephone: +44
(0)207 5945820. E-mail: a.demello@ic.ac.uk.
(1) Lamberts, J. J. M.; Neckers, D. C. Tetrahedron 1985, 41(11), 2183.
(2) Nickon, A.; Mendelson, W. L. J. Am. Chem. Soc. 1965, 87, 3921.
(3) Redemann, E. G. J. Am. Chem. Soc. 1942, 64, 3049.
(4) Wilk, I. J. J. Chem. Educ. 1968, 45, A547.
(6) Jensen, K. F. Chem. Eng. Sci. 2001, 56, 293.
(5) Scharf, H.-D.; Esser, P.; Kuhn, W.; Pelzer, R. U.S. Patent 5,620,569, April
15, 1997.
(7) Mitchell, M. C.; Spikmans, V.; de Mello A. J. Analyst 2001, 126, 24.
(8) Sirichai, S. C.; de Mello, A. J. Analyst 2000, 125, 133.
10.1021/op0155155 CCC: $22.00 © 2002 American Chemical Society
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for use. It should be noted that oxygen and air are considered
interchangeable for many (although not all) singlet oxygen
preparations, although an adjustment in flow rate would have
to be made to compensate for the lower partial pressure of
oxygen in air. Rose Bengal is readily recyclable, so that
relatively high concentrations of sensitiser are not necessarily
a cost issue. Furthermore, since the effective optical path
length is 50 µm, a high sensitiser concentration does not pose
any experimental problems. The molar extinction coefficient
of Rose Bengal in methanol is 99 800 cm-1 M-1 at 550 nm.
Despite this high value a concentration of 5 × 10-3 M Rose
Bengal yields a total absorbance of 0.025 (equating to a
transmittance of approximately 95%). This means that
molecules at any position within the irradiation zone will
experience a broadly similar photon flux. Consequently, the
use of a microfabricated reactor actually facilitates the use
of high sensitiser concentrations, which is desirable in most
circumstances.
In addition, it should be noted that the small cross section
of the reactor channels results in effective irradiation even
from relatively low-intensity light sources. This leads to
reduced sample heating and therefore reduced radical
recombination. Efficient transformation (>80% conversion
of feedstock by GC area analysis as described) can be
achieved with an irradiation (reaction) time of less than 5 s.
Figure 2 shows typical GC traces of the chip feedstock
solution and the chip product after work-up. Although the
method of analysis is crude, the identification of the product
peak by separately synthesised authentic ascaridole renders
it less ambiguous.
It is likely than the majority of microfluidic devices will
eventually be structured from polymeric materials (rather than
silicon or glass) due to the wide availability of base materials,
commercial chip manufacturers, and highly cost-effective
fabrication methods (such as injection molding and hot-
embossing). This means that the reactor chips described
herein may be “printed” and bonded en masse at low unit
cost.10 Furthermore, since light can penetrate the substrate
material from any direction and the chips function perfectly
in any orientation, large arrays of chips can be linked together
to form three-dimensional structures surrounding light sources.
Altering the size of the serpentine section will also allow
for faster flow rates with similar irradiation times.
In conclusion the use of a microfabricated nanoreactor
to effect the safe, continuous generation and reaction of
singlet oxygen has been demonstrated. The technique avoids
the major dangers inherent in the method and allows for
reliable reaction even with relatively low-intensity light
sources.
Figure 1. Schematic of reactor chip for singlet oxygen
reactions.
plate, with holes drilled for external access, was cleaned in
H2SO4/H2O2 and aligned before contact with the etched glass
substrate. To form enclosed channels, the plates were
thermally bonded in an oven.
The reactor channel pattern is schematically described in
Figure 1. The chip consists of a divergent inlet channel (A),
a secondary inlet channel (B), a serpentine irradiation sector,
and an outlet channel (C). The etched channels have an
average depth of 50 µm and an average width of 150 µm.
The serpentine section has a total length of 50 mm.
Results and Discussion
Under the reaction conditions optimised for the reactor
chip no presaturation of the R-terpinene solution with oxygen
was necessary, meaning that at any given instant the total
volume of oxygenated solvent could be measured in picoli-
tres. This small volume of oxygenated solvent present at any
one time minimises the risks involved in the synthesis.
Furthermore, nitrogen degassing of chip effluent can be
undertaken as soon as the effluent is collected, to avoid
accumulation of oxygenated solvents or the elevation of
oxygen saturation in the reactor surroundings.
To effect the synthesis of ascaridole from R-terpinene the
delay section was irradiated using an unfiltered, 20-W, 6-V
overhead tungsten lamp on an inverted microscope stage
(Leica DMIL, Milton Keynes, UK). A solution of sensitiser
dye and terpinene in methanol was introduced through A,
and a stream of oxygen was introduced through B. The
effluent was collected at C and worked up by diluting 10:1
with diethyl ether, passing through a silica plug, and
evaporating off the excess solvent with a stream of nitrogen.
Transformation was monitored using capillary gas chroma-
tography (GC), utilising a HP Innowax stationary phase. GC
samples were introduced using an autosampler and a HP
68190 autoinjector array to avoid operator errors. Samples
were compared to a sample of ascaridole prepared by
standard methods that had been characterised by spectral
comparison to literature data.9 Samples thus prepared co-
ran in GC analysis with chip-produced products. Crude
material from the microchip effluent was submitted to NMR
analysis and demonstrated ascaridole present as the majority
product.
Experimental Section
Reagents and solvents were obtained from commercial
sources and used as received.
Continuous Flow Synthesis of Ascaridole. A solution
of R-terpinene (85%, 0.6 mL) and Rose Bengal (certified,
0.1 g) in methanol (20 mL) was prepared. This solution was
introduced into inlet A of the reactor chip at a flow rate of
In common with laboratory-scale procedures pure oxygen
and a relatively concentrated sensitiser solution were chosen
(9) Backhouse, J. R.; Lowe, H. M.; Sinn, E.; Suzuki, S.; Woodward, S. J.
Chem. Soc., Dalton Trans. 1995, 9, 1489.
(10) Becker, H.; Gartner, C. Electrophoresis 2000, 21, 12.
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Figure 2. GC traces of (a) chip feedstock solution, (b) chip effluent.
1 µL/min. Pure oxygen was introduced into inlet B of the
reactor chip at a flow rate of 15 µL/min. Both were
NMR (Bruker 250 MHz) δ 0.99 (6H, d, J ) 6 Hz), 1.37 (3H, s),
1.49-1.56 (2H, m), 2.01 (1H, hept, J ) 6 Hz), 2.02-2.05
(2H, m), 6.41 (1H, d, J ) 8 Hz), 6.49 (1H, d, J ) 8 Hz) ppm.
introduced using a Hamilton PHD 2000 syringe pump. The
serpentine section of the chip was irradiated at full power
using the microscope overhead lamp as described at a
distance of 10 cm from the reactor surface and the product
collected in a brown glass vial. The product was diluted 10:1
with diethyl ether and passed through a short silica plug,
and the solvent was evaporated using a nitrogen stream. The
product was analysed by GC giving a conversion by area
analysis of 85%, and a crude NMR spectrum was obtained.
Laboratory Synthesis of Ascaridole. R-Terpinene (1
mL), Rose Bengal (0.2 g), and methanol (40 mL) were
combined in a 100-mL round-bottomed flask fitted for reflux.
Oxygen was bubbled through the mixture for 5 min and then
the flask was illuminated with a 500-W tungsten lamp at a
distance of 20 cm from the flask. Illumination and oxygen-
ation were continued for 4 h. The mixture was evaporated,
and then the residue was dissolved in diethyl ether (20 mL)
and filtered through a short silica plug. The resulting solution
was concentrated and purified by flash chromatography on
silica (hexane eluent, Rf ) 0.65) giving ascaridole (0.7 g,
67%).
MS
(C. I. Ammonia) m/z 186 (MNH4+), 169 (MH+)
152, 135, 121, 109, 93
GC
HP Innowax capillary GC column, 30 m in length.
Helium carrier gas operating at a flow rate of 1.3 mL/min
inlet temperature: 300 °C
column temperature: 60 °C, maintained for 3 min, then ramped
at 40 °C/min to a maximum of 230 °C, maintained for 10 min
retention times: R-terpinene 6.30 min, ascaridole 10.26 min
Acknowledgment
We thank EPSRC UK, the Department of Trade and
Industry (DTI), Lab-on-a-Chip Consortium for financial
support. R.F. is grateful to SmithKlineBeecham Pharmaceu-
ticals for an EPSRC CASE studentship.
Supporting Information Available
NMR and MS spectra for ascaridole (bulk method), crude
NMR for ascaridole (continuous synthesis). This material is
available free of charge via the Internet at http://pubs.acs.org.
Received for review November 1, 2001.
OP0155155
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