Rapid formation of amides via carbonylative coupling reactions using a microfluidic device

Article abstract of DOI:10.1039/b515710b

Carbonylative cross-coupling reactions of arylhalides to form secondary amides were rapidly carried out on a glass-fabricated microchip - the first time a microstructured device has been used to perform a gas-liquid carbonylation reaction. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b515710b

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Rapid formation of amides via carbonylative coupling reactions using a
microfluidic device
Philip W. Miller,a Nicholas J. Long,a Andrew J. de Mello,a Ramon Vilar,b Jan Passchierc and Antony Geec
Received (in Cambridge, UK) 8th November 2005, Accepted 21st November 2005
First published as an Advance Article on the web 15th December 2005
DOI: 10.1039/b515710b
and can take many hours to reach completion. The rates of these
reactions are dependent on a number of factors such as the
arylhalide species, the nature of the catalyst, the nucleophilic
species, the pressure and the temperature of the system. The
insertion step of the carbonylative catalytic cycle (Scheme 2) can be
rate limiting due to the poor transport of carbon monoxide into
the solution phase. This step of the catalytic cycle can be enhanced
by using high pressure reactors, however, such reactors are
inherently expensive and require special safety precautions.
Microreactor devices provide an unexplored and potentially very
useful alternative method for carrying out these gas–liquid phase
carbonylation reactions.
Carbonylative cross-coupling reactions of arylhalides to form
secondary amides were rapidly carried out on a glass-fabricated
microchip—the first time a microstructured device has been
used to perform a gas–liquid carbonylation reaction.
Microstructured devices are finding ever more innovative applica-
tions in chemical synthesis and chemical engineering.1 A key
feature of such devices is their increased surface area-to-volume
ratio which is a direct result of their decrease in physical size.
Specific surfaces of microstructured devices can be as high as
50 000 m2 m23 whereas conventional laboratory apparatus does
not usually exceed 1000 m2 m23. A consequence of this increase in
specific surface is the enhancement of mass and heat transport in
the system. Microreactors specifically designed for multiphase gas–
liquid and gas–liquid–solid reactions have been used to carry out a
range of reactions, including oxidation,2 fluorination,3 nitration4
and hydrogenation5 reactions, all of which have shown enhanced
rates, yields and/or selectivities, compared to their corresponding
batch reactions. These improvements are attributed to the
increased interfacial contact area generated between the phases
within the reactor. The advantages of using microreactors for gas–
liquid reactions are particularly appealing and could be applied to
a number of other reaction systems. We report here, for the first
time, the synthesis of secondary amides via the carbonylative cross-
coupling of arylhalides with benzylamine using carbon monoxide
gas (Scheme 1) in a glass fabricated microstructured reactor.
The insertion of carbon monoxide into an organic molecule
(known as carbonylation),6 is a convenient but underdeveloped
synthetic route to a number of common functional groups
including amides, esters, lactams and lactones.7 Carbonylation
reactions are usually carried out at high pressures using carbon
monoxide gas in the presence of a palladium–phosphine catalyst
Our microfluidic device was constructed from a glass substrate
using chemical wet etching techniques.{ The liquid and gaseous
reagents are mixed on the chip using a mixing-tee configuration.
The reaction channel is 5 m long and has an average width of
200 mm and average depth of 75 mm, giving a total volumetric
capacity of 75 ml. The area taken up by the microchannel footprint
on the glass substrate is approximately 50 mm 6 50 mm (Fig. 1).
The liquid reagents, consisting of a mixture of arylhalide,
palladium–phosphine catalyst and benzylamine, were infused into
the chip at rates of 20, 10 or 5 ml min21 while the gas flow was kept
constant at 2 sccm.{ An annular flow regime is imposed on the
system at these flow rates whereby a thin film of liquid is forced to
the surface walls of the microchannel while the gas flows through
the centre, this generates a very high interfacial area. This flow
pattern was found to be the easiest to reproduce; other flow
patterns, such as slug flow, were difficult to control over the length
of experimental timescale. Three different arylhalide substrates
(iodobenzene 1a, 4-iodoanisole 1b and 2-bromopyridine 1c) were
Scheme 1 The synthesis of N-benzylbenzamides via carbonylative
cross-coupling.
aDepartment of Chemistry, Imperial College London, London, UK
SW7 2AZ. E-mail: n.long@imperial.ac.uk; Fax: +44 (0)20 75945804;
Tel: +44 (0)20 75945781
bInstitute of Chemical Research of Catalonia (ICIQ), Avgda. Paisos
Catalans 16, 43007 Tarragona, Spain. E-mail: rvilar@iciq.es;
Fax: +34 977 920 228; Tel: +34 977 920 212
cPET Imaging Division, Translational Medicine and Genetics,
GlaxoSmithKline, Academic Centre for Clinical Investigation,
Addenbrooke’s Hospital, Hills Road, Cambridge, UK CB2 2GG
Scheme 2 Catalytic cycle for the carbonylation reaction.
546 | Chem. Commun., 2006, 546–548
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Fig. 2 a-Ketoamide product, resulting from the double carbonylation
reaction.
produced in the system. The initial carbon monoxide backpressure
in the system varied between 3 and 4 bar, depending on the liquid
infusion rate. Both of these factors will increase the carbon
monoxide solubility and therefore benefit the insertion step of the
catalytic cycle.
An interesting side product from the reaction is the a-ketoamide
derivative (Fig. 2), formed by a double carbonylation mechanism.8
The a-ketoamide formation was observed for substrates 1a and 1b
but not for 1c. Surprisingly, the a-ketoamide was the main product
formed by reaction of 1b. No a-ketoamide formation was
observed in the batch reactions. As the reaction was not optimised
for the formation of the a-ketoamide product it may be possible to
enhance its formation by tailoring the reaction conditions through
varying the amount of catalyst and the gas/liquid infusion rates.
Yields obtained for the carbonylation of substrate 1b are lower
than those of 1a and 1c. This is due to the introduction of an
electron donating methoxy group on the para postion of the
phenyl ring. Electron donating groups on arylhalides are generally
known to slow down the oxidative addition step of the catalytic
cycle and therefore give lower yields. The formation of the
a-ketoamide as the major product for the reaction of 1b is due to
an enhanced CO insertion rate relative to nucleophilic attack by
base as a result of the decreased electrophilicity of the CO-
coordinated aryl–palladium complex.8c In contrast, substate 1c
shows exclusive formation of the amide, no formation of the
a-ketoamide product is observed due to the electron withdrawing
nature of the pyridine ring. The gas chromatograms were run after
acidic work-up and extraction, therefore any product (N-aryl
amine) from a competitive Buchwald-type amination reaction
would have been removed in the acidic layer and not be observed
on the GC trace. However, unreacted arylhalide was observed in
the GC traces, and as suggested by one of the referees a second
pass through the reactor or a longer channel should improve
overall yields. We intend to investigate further the competitive
nature of this type of amination reaction.
Fig. 1 A photograph of the microfluidic chip used in the carbonylation
reactions prior to chromium removal and bonding.
used to test the microreaction carbonylation procedure; the
resulting yields are shown in Table 1.
The mean residence time of the microreactions was estimated to
be less than 2 min for all the flow rates, based on the timing of
fluorescent dyes through the chip.§ The length of the chip device
(5 m) is necessary to give the reagents enough time within the
channels of the device to react due to the gas forcing the liquid out
of the chip, initial experiments using devices with shorter channels
(, 2 m) showed only trace amounts of product. Batch reactions
were carried out over a ten minute time period to assess the
performance of the microreactor." The microreactions, even with
their much shorter residence times, show an increase in yield when
compared to the batch reactions. When the liquid infusion rates
are relatively high (20 ml min21) modest yields of these
conventionally slow reactions are obtained in a very short time
period. Reduction of the flow rate to 5 ml min21 leads to a slight
gain in observed product yield. We believe this to be due to a more
even distribution of the liquid reagents on the chip’s walls forming
a more stable annular flow regime.
The increase in yield of the microreactions can be attributed to
two factors, the increased interfacial gas–liquid contact area
generated within the microstructured reactor and an increase in
carbon monoxide pressure resulting from the backpressure
Table 1 Carbonylation reactions of iodobenzene 1a, 4-iodoanisole 1b
and 2-bromopyridine 1c, under the microreactor and batch reaction
conditions
In summary, for the first time a microstructured device has been
used to perform a gas–liquid carbonylation reaction. The total
yields of products obtained are good considering the very short
residence times (, 2 min) for these conventionally slow reactions.
When compared to traditional batch scale reactions, the gains in
yields over this time period obtained by the microreactor are
significant and demonstrate a distinct advantage in using such
methods. Space–time yields (mol l21 h21) achieved by the
microreactions are over an order of magnitude greater than the
batch reactions. Improvements in yields for these reactions could
be achieved by optimising the reaction conditions and catalysts.
Specialist uses of these microreaction systems could be applied to
catalyst screening9 or in rapid radiolabelling techniques,10 such as
applied in Positron Emission Tomography, where the focus is
centred on fast chemical syntheses.
Infusion
Yield of
Yield of
Total
Substrate rate/ml min21 amide (%)a a-ketoamide (%)a yield (%)
1a
20
10
5
—
20
10
5
—
20
10
5
31
37
46
25
10
10
12
11
46
51
58
18
18
17
9
49
54
55
25
30
29
40
11
46
51
58
18
batch
1b
0
20
19
28
0
0
0
batch
1c
0
0
batch
a
—
Yields were determined by GC analysis.
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Chem. Commun., 2006, 546–548 | 547

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Notes and references
{ A soda lime glass substrate with a positive photoresist and a low
reflective chromium layer was exposed using a direct-write laser
lithographic system (DWL 2.0, Heidelberg Instruments, Heidelberg,
Germany) to transfer the channel design. The photoresist was chemically
developed and the channels of the design etched into the glass using HF–
NH4F solution. External holes were drilled at the reagent entry and exit
points. The substrate was then cleaned to remove the excess chromium,
soaked in concentrated sulfuric acid and rinsed with deionised water prior
to thermal bonding of the glass cover plate.
{ In a typical reaction a (1 M) solution of arylhalide (0.5 mmol) in
benzylamine (0.5 ml) and palladium catalyst (Pd(dppp)Cl2, 2 mol%) was
infused into a microfluidic chip at flow rates of 20, 10 or 5 ml min21 where
it was mixed with a steady stream of CO gas, metered at 2 sccm using a
Sierra 100 series Smart-Trak mass flow controller. The chip was heated to
80 uC using a heating block. The solution was collected into a vial
containing HCl (1 M) to quench the reaction and extracted using
dichloromethane (2 6 5 ml). Quantitative analysis was done by gas
chromatography. Reference amide materials were synthesised using a
similar procedure to Schoenberg and Heck,7a reference a-ketoamide
materials were synthesised by a procedure similar to that used by Guo
et al.11
§ Chip residence times were estimated by injecting a 20 ml slug of
fluorescein into a continuous flow of water at infusion rates of 20, 10 and
5 ml min21 at gas (air) flow rates of 2 sccm. The fluorescent dye was timed
from its initial entry onto the chip until its exit; at all infusion rates
residence times were less than two minutes.
" To a Schlenk flask was added a (1 M) solution of arylhalide (0.5 mmol)
in benzylamine (0.5 ml) and palladium catalyst (Pd(dppp)Cl2, 2 mol%). The
flask was then placed under an atmosphere of carbon monoxide (filled and
evacuated three times). The reaction flask was then placed into a preheated
oil bath (80 uC) and stirred vigorously for 10 min. After this time the
carbon monoxide atmosphere was removed and the reaction worked-up
and analysed in the same way as for the microreaction.
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Microreactors: New Technology for Modern Chemistry, Wiley-VCH,
Weinheim, 2000.
548 | Chem. Commun., 2006, 546–548
This journal is ß The Royal Society of Chemistry 2006