Additionally, the low manufacturing cost of the device
provides the option to use it as a disposable component,
despite the fact that the MFDs exhibited sufficient robustness
to enable extended and repeated usage. MFDs are able to
operate at elevated pressure, provide excellent temperature
control and fast heat transfer, and can offer a controlled
residence/reaction time between seconds and hours.
a system is poised to have a considerable impact on chemistry
synthesis programs in the future.
Experimental Section
Starting materials, reagents, and solvents were obtained
from commercial suppliers and were used without further
1
purification. H NMR spectra were recorded on a Bruker
Avance DPX-400 spectrometer with residual chloroform as
the internal reference (δ ) 7.26 ppm).
Oxazole Formation 4. Three sets of feed solutions were
prepared for the synthesis of three different oxazoles: (a)
MFDs can sustain higher pressures than standard labora-
tory glassware reactors. The small dimensions of the system
mean that pressurised flows within the MFD can be generated
due to the high flow resistance of the microchannels, thus
yielding beneficial effects in terms of higher boiling points,
greater solubility, and higher diffusion rates. The high
surface/volume ratio has the potential to be exploited in
reactions using functionalised capillary walls, ideal for the
4
-(3-nitro benzyl)-5-(ethylaceto)oxazole ethyl isocyanoac-
etate 1 (0.1 mol/L in MeCN), 3-nitrobenzoyl chloride 2
0.125 mol/L in MeCN); (b) 4-(4-bromobenzyl)-5-(ethylac-
(
eto)oxazole ethyl isocyanoacetate 1 (0.5 mol/L in MeCN),
4-bromobenzoyl chloride 2 (0.5 mol/L in MeCN); and (c)
1
7
immobilisation of reagents, catalysts, and scavengers. The
melt-extrudable polymers, polyvinyl alcohol (PVA) and
polystyrene (PS), are suitable materials for the preparation
of MFDs with functionalised capillary surfaces. Their
development is currently under investigation. The use of
polymers such as polyethylene (PE), fluorinated ethylene
propylene (FEP), or perfluoroalkoxy polymer resin (PFA)
which are relatively opaque to microwave irradiation would
enhance flow microwave chemistry applications. Preliminary
experiments using LLDPE MCFs as a continuous-flow
system within a focused laboratory microwave unit (Emrys
Optimizer) have shown promise. However, a disadvantage
of MFDs is their low thermal stability. The fact that they
are made from thermoplastics will inevitably limit the
temperature range of application for reactions at typically
below 150 °C. Solvent resistance of the MCF matrix might
also be an issue for certain polymers. However, tests with
LLDPE films, which were used within the three case studies
of this paper, have shown a good resistance to many
commonly used solvents, such as ethers, alcohols, acetoni-
trile, DCM, and toluene. MFDs made from fluorinated
polymers, such as PFA or FEP, would offer sufficiently high
solvent stability for almost all organic processes.
4
1
-(4-iodobenzyl)-5-(ethylaceto)oxazole ethyl isocyanoacetate
(0.1 mol/L in MeCN), 4-iodobenzoyl chloride 2 (0.1 mol/L
in MeCN). A 1-mL sample of each solution was simulta-
neously injected into the two feed lines, mixed in a T-piece,
and fed into the MFD. An Omnifit 0.34 mL-glass tube
cartridge was filled with 0.3 g of PS-BEMP (2-tert-
butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-di-
azaphosphorine on polystyrene) and put in line following
the MFD. The total flow rate through the reactor was set to
0
1
.19 mL/min, resulting in residence times on the MFD of
19 min. The reactor set-up was operated at ambient
temperature. The product solution which was collected at
the outlet of the packed-bed column was removed on a
VapourTech V10 solvent evaporator. H NMR spectra were
1
3
taken of the white crystalline product using d -chloroform
as a solvent, leading to the following conversions and
yields: (i) 4-(3-nitrobenzyl)-5-(ethylaceto)oxazole: quantita-
tive conversion, 99% yield; (ii) 4-(4-bromobenzyl)-5-(ethy-
laceto)oxazole: 75% conversion; and (iii) 4-(4-iodobenzyl)-
5
-(ethylaceto)oxazole: quantitative conversion.
Salicylaldehyde Allyl Ether 6. Two feed solutions were
prepared, (1) salicylaldehyde 5 (73.26 g; 2 mol/L) and DBU
185.16 g; 4 mol/L) in a total volume of 300 mL of MeCN
(
With the experiments described in this article, we have
shown that MFD technology has certain strategic advantages
over other microreactor designs such as longer reactor length
and (2) allyl bromide (145.20 g; 4 mol/L) in a total volume
of 300 mL of MeCN. The two feed solution streams were
pumped into the reactor and continuously mixed in a T-piece
before being fed into the eight MFDs running in parallel.
The total flow rate through the reactor was set to 2 and 4
mL/min, resulting in residence times on the MFD of 113
and 57 min, respectively. The reactor was operated at ambient
temperature. An aqueous extraction was carried out on the
product solution in order to remove salt and excess base from
the product stream. This was either carried out in batch, using
standard laboratory glassware, or in continuous mode, using
a flow liquid-liquid extraction set-up. For the latter, the
organic product solution was mixed on a glass microreactor
chip (Syrris 274 µL) with an equal amount of aqueous HCl
(10 mol %) and then fed into a membrane separator (Syrris
FLLEX) to separate both phases again. Two HPLC pumps
(leading to longer reaction times) and its low manufacturing
costs. Although in the above experiments all the parallel
capillary tubes have been used to process the same chemical
inputs, in principle each capillary could function as an
independent reactor. We believe that the evolution of such
(
16) (a) Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. J. Chem. Soc., Chem.
Commun. 2005, 2909. (b) Saaby, S.; Baxendale, I. R.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 3365. (c) Baxendale, I. R.; Deeley, J.; Ley, S. V.;
Griffiths-Jones, C. H.; Saaby, S.; Tranmer, G. K. J. Chem. Soc., Chem.
Commun. 2006, 2566. (d) Baxendale, I. R.; Griffiths-Jones, C. H.; Ley, S.
V.; Tranmer, G. K. Synlett 2006, 427. (e) Baxendale, I. R.; Griffiths-Jones,
C. H.; Ley, S. V.; Tranmer, G. K. Chem.-Eur. J. 2006, 12, 4407. (f)
Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. J. Chem. Soc.,
Chem. Commun. 2006, 46, 4835. (g) Smith, C. D.; Baxendale, I. R.;
Tranmer, G. K.; Baumann, M.; Smith, S. C.; Lewthwaite, R. A.; Ley, S. V.
Org. Biomol. Chem. 2007, Published on the Internet http://dx.doi.org/
10.1039/b702995k. (h) Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward,
(Knauer K-120) provided the flow for this set-up. The flow
J. J.; Smith, S. C.; Ley, S. V. Org. Biomol. Chem. 2007. Published on the
Internet http://dx.doi.org/10.1039/B703033A.
rates were set to a maximum of 1.5 mL/min for each line in
order to achieve a sufficiently good separation. Afterwards
the solvent was removed on a VapourTech V10 solvent
(
17) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.;
Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J.
Chem. Soc., Perkin Trans. 1 2000, 23, 3815.
404
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Vol. 11, No. 3, 2007 / Organic Process Research & Development