Modular microreaction systems for homogeneously and heterogeneously catalyzed chemical synthesis

Article abstract of DOI:10.1002/hlca.200490304

Until now, microreaction devices designed for a specific type of reaction were used mainly for highly exothermic, very fast reactions. Described is a modular microreaction system and its application to representative homogeneous and heterogeneous reactions important in organic synthesis. The modular microreaction system allows continuous flow processes to be optimized and employed effectively in the chemical laboratory. The modular microreaction systems proved also versatile for syntheses requiring moderate reaction times, thus extending their application to a large fraction of organic reactions. The use of the modular and cleanable microreaction systems to rapidly develop optimized reaction conditions provides an excellent basis for the development of many chemical transformations scalable from milligram to ton production quantities.

Full text of DOI:10.1002/hlca.200490304

Helvetica Chimica Acta ± Vol. 88 (2005)
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Modular Microreaction Systems for Homogeneously and Heterogeneously
Catalyzed Chemical Synthesis
by Daniel A. Snyder1), Christian Noti, and Peter H. Seeberger*1)
Department of Chemistry, Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule,
ETH-Hönggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich
and Frank Schael, Thomas Bieber, Guido Rimmel, and Wolfgang Ehrfeld
Ehrfeld Mikrotechnik AG , D-55342 Wendelsheim
Until now, microreaction devices designed for a specific type of reaction were used mainly for highly
exothermic, very fast reactions. Described is
a modular microreaction system and its application to
representative homogeneous and heterogeneous reactions important in organic synthesis. The modular
microreaction system allows continuous flow processes to be optimized and employed effectively in the
chemical laboratory. The modular microreaction systems proved also versatile for syntheses requiring moderate
reaction times, thus extending their application to a large fraction of organic reactions. The use of the modular
and cleanable microreaction systems to rapidly develop optimized reaction conditions provides an excellent
basis for the development of many chemical transformations scalable from milligram to ton production quantities.
1. Introduction. ± Microfabricated reaction systems (microreaction systems) have
generated much interest in recent years for use in analysis in the chemical and
biological sciences [1]. The reduced size of such microanalytical systems minimizes the
required sample size and facilitates experimental throughput and automation. Micro-
reaction systems have also been explored for use in chemical synthesis [2], where high
heat-and masst-ransfer rates have been exploited to perform reactions otherwise
considered dangerous [3]. Initial explorations in combinatorial chemistry have been
reported as well [4]. The use of microreaction systems for fine chemical synthesis is just
evolving [5]. The synthesis of key intermediates or active drug molecules in the
chemical and pharmaceutical industries could benefit from microreaction systems by
enabling cost-effective transition from bench-top to production scale. Microstructured
reactors (microreactors) are essential parts of microreaction systems and have been
explored extensively [6]. However, to fully benefit from microreaction technology,
microreaction systems should incorporate common unit operations of chemical
engineering such as mixing and heat exchange in one unit. Ideally, such microreaction
systems would be i) fully modular to allow for quick transfer of reactions developed for
batch operation mode, be ii) easily assembled for experimental flexibility, and iii)
enable significant production rates for both homogeneous and heterogeneous reactions
at elevated temperatures and high pressures on a table top.
Here, we describe a modular microreaction system and its application to
representative homogeneous and heterogeneous reactions important in organic
1
)
Former address: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139,
USA.
ꢀ 2005 Verlag Helvetica Chimica Acta AG, Zürich

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synthesis. The modular microreaction system allows continuous flow processes to be
optimized and employed effectively in the chemical laboratory. Syntheses enabled by
the modular microreaction system in the laboratory environment are readily scalable.
The continuous operation mode avoids scale-up difficulties typically encountered when
lab-scale batch processes are be transferred to production-scale processes [7]. In
addition, the microstructures inserted in the modules of the modular microreaction
system are scalable by increasing the number of parallel microstructures without
changing the characteristic dimensions. In this way, process conditions may be main-
tained while adjusting modular microreaction systems to the desired production rates.
2. Results and Discussion. ± The modular design of the microreaction system allows
one set of components to be used for a variety of purposes, thus accelerating the
development of protocols for new reactions. The modules of the modular microreaction
system were composed of mechanically machined approximately cubic stainless steel
blocks (25 mm) containing stainless steel inserts with characteristic dimensions of 50 ±
100 mm for fluid-handling functions. The passive total fluidic volume of the modular
microreaction system was minimized by avoiding any connectors or pipes between the
unit operation modules, which were sealed against each other by chemically resistant
O-rings that withstand pressures of up to 100 bar. The modular microreaction system
employed here was designed for flow rates of up to 100 ml/min.
Basic features of the modular microreaction system are the ability for reactive
mixing of components on a mm length scale, followed by subsequent diffusional and
secondary flow mixing in micromixers. The micromixers operate via interdigitating
streams of solvent. They allow for the combination of reactant streams in milliseconds
to seconds depending on the diffusion coefficients and flow conditions, thereby
minimizing local concentration gradients that may result in side-product formation. In
general, reaction selectivity and yield can be sensitive to mixing effects when the
reaction rate is higher than the mixing rate [8]. For the reactions described below, it was
assured that mixing rates of the micromixers were 1 ± 2 orders of magnitude higher than
the reaction rates. The modular microreaction systems allow also for precise control of
reaction conditions including temperature, pressure, and residence time. The cross-type
heat-exchangers facilitate rapid, intensive heating and cooling to reach the optimal
reaction temperature. The capillary reactor used as general-purpose residence time
module for liquids employed a temperature controlled stainless steel capillary reactor
consisting of a capillary with 1-mm internal diameter. The multiple-turn coiling of the
reactor capillary was designed to result in a residence-time distribution of the reaction
medium in the reactor that is half as broad as the corresponding residence-time
distribution in a non-coiled capillary of the same length. A cartridge reactor allows a
solid catalyst to be enclosed in a temperature controlled, flow-through stainless steel
cartridge.
The simple modular microreaction system employed here included two heat-
exchangers, a micromixer, and a temperature-controlled capillary reactor consisting of
either a 1.7 and 4 ml volume capillary, respectively, or a 0.5-ml cartridge reactor
charged with solid catalyst (Fig. 1).
Two reactant solutions were fed through the micromixer into the reactor using
HPLC pumps with flow rates between 0.07 and 4 ml/min, and the eluent from the micro-

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Fig. 1. Modular microreaction system with a 0.5-ml cartridge reactor (module equipped with electrical cables)
for employment of solid catalysts. Alternatively, an arrangement with a capillary reactor (not shown) was used
for homogeneous and heterogeneous liquid/liquid reactions.
reaction system was quenched immediately. Exemplary, Fourier transform infrared
(FT-IR) absorbance spectra of modular microreaction systems eluents were collected
in-line via an attenuated total reflection (ATR) flow-through cell with adjacent FT-IR
spectrometer.
Several representative chemical transformations were carried out including
acylation, alkylation, cycloaddition, olefination, and cross-coupling reactions (Table).
For the aldol condensation, a more-complex reactor configuration was employed.
In a first micromixer, acetone and PhCHO were mixed before KOH was added in a
second mixer. The mixture was subsequently fed into the capillary reactor. After
passing through the reactor, AcOH was added by a third micromixer to quench the
reaction. Finally, CHCl3 was added in a fourth micromixer to extract the product, and
the eluent was collected in a flask to allow for phase separation.
Initially, acetylation of 2-phenylethanol using excess Ac2O and 4-(dimethylami-
no)pyridine (DMAP) as catalyst was explored; with a residence time of 15 min in the
capillary reactor, the reaction resulted in 95% yield of product as measured by GC-FID
of the quenched, extracted, and dried reactor eluant2). Alkylation of PhOK by
PhCH2Br with an excess of PhOK in DMF was found to be extremely rapid (residence
2
)
To produce 2-phenylethyl acetate, a solution of Ac2O (0.7 ml, 7.70mmol) in pyridine (25 ml) and a
solution of 2-phenylethanol (0.33 ml, 2.76 mmol) and DMAP (25 mg, 0.20 mmol) in pyridine (25 ml) were
combined during a residence time of 15 min at 308. A 1.8-ml portion of the reactor eluant was collected
into 1m HCl (20 ml) for analysis; this was extracted with Et2O (15 ml), and the organic layer was washed
with 5% Na2CO3 (3 ml), dried (Na2SO4), and analyzed by GC, which showed the product to have been
formed in 95% yield.

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time 1 min) and resulted in quantitative yield. Interestingly, this reaction could also be
carried out under biphasic conditions (CHCl3/H2O) in the presence of Bu4NI (TBAI)
as phase-transfer catalyst, but required a longer reaction time. It should be noted that
the capillary reactor was not explicitly designed for biphasic liquid ± liquid reaction
media, which tend to separate spontaneously. While reactors designed for such media
were described previously [9], these media were not further investigated in the present
work.
Next, we demonstrated the utility of the microreaction systems to carry out C ± C
bond-forming reactions at elevated temperatures. The Diels ± Alder reaction of maleic
anhydride with excess 2,3-dimethylbuta-1,3-diene proceeded readily [10]. Horner ±
Wadsworth ± Emmons olefination of PhCHO with triethyl phosphonoacetate also
caused no problems; 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) was found to perform
better than 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), resulting in 91% yield in 10 min
at 508. For a conventional batch process under slightly different conditions, a yield of
85% was reported [11]. TBD also efficiently catalyzed a Henry nitroaldol addition,
whereby the reaction temperature showed little influence between 0 and 508 [12].
Metal-catalyzed cross-couplings are key transformations for the assembly of
complex molecules. Therefore, we explored the applicability of microreaction systems
to these important modes of bond formation. Heck coupling of PhI and ethyl acrylate
using Pd on charcoal on 20-mmol scale without preconditioning afforded 99% yield of
the desired ethyl cinnamate in 30 min at 1308 [13][14]. Batch methods had resulted in
100% conversion after 30 min at 1408 with preconditioned catalyst [15].
During the optimization of chemical syntheses and the development of industrial
processes, it is important to gain a sound understanding of the reaction mechanism. The
aldol condensation of acetone and PhCHO was studied and optimized using modular
microreaction systems with regard to reactant concentrations and reaction time. The
dependence of the yield of benzylidene-acetone (ˆ4-phenylbut-3-en-2-one; Table and
Fig. 2) for various reaction times and stoichiometric ratios of the reactants was
recorded.
The highest yield of benzylidene-acetone (59%) and dibenzylidene-acetone (ˆ1,5-
diphenylpenta-1,4-dien-3-one; 20%) was obtained with a reaction time of just 7 min
and a twofold excess of PhCHO. Under these conditions, acetone was almost
completely consumed (99% conversion).
Yield and selectivity of a reaction can be optimized readily using modular
microreaction systems but required a total of 34 h in the laboratory to perform 59
measurements in 13 set-ups. A similar optimization carried out with conventional
laboratory equipment would require 65 h of laboratory work when assuming that each
set-up would require 5 h of work. It should be mentioned that other parameters such as
pressure can be varied and optimized with the modular microreaction system within the
same time-frame. High yields and selectivities were observed throughout the series of
homogeneous and heterogeneous reactions (Table) underlining the broad applicability
of the modular microreaction systems.
GC Analysis was the most time-consuming part of these studies. In-line
spectrometric techniques may further accelerate reaction optimization as demonstrat-
ed for the Henry reaction (Fig. 3, and Table), where in-line FT-IR was applied.
Conversion was measured by FT-IR as a function of process parameters such as

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Fig. 2. Actual yield of non-isolated benzylidene-acetone obtained with the modular microreaction system for
various concentrations of acetone and benzaldehyde, and reaction times. The reaction time was varied by
variation of the total flow through the modular microreaction system. The black bars indicate the results with
maximized yield of benzylidene-acetone.
reaction time (see inset of Fig. 3). The results were in good agreement with results
obtained by GC. The combination of modular microreaction systems with rapid, non-
invasive analysis methods provides an elegant way for on-line optimization and
statistical analyses of chemical syntheses.
3. Conclusions. ± Until now, microreaction devices designed for a specific type of
reaction were used mainly for highly exothermic, very fast reactions. The modular
microreaction systems proved also versatile for syntheses requiring moderate reaction
times, thus extending their application to a large fraction of organic reactions. The use
of the modular and cleanable microreaction systems to rapidly develop optimized
reaction conditions provides an excellent basis for the development of many chemical
transformations scalable from milligram to ton production quantities.
Experimental Part
General. All microreaction modules were manufactured by Ehrfeld Mikrotechnik (Ehrfeld Mikrotechnik
AG, D-55342 Wendelsheim). The cross-current flow heat-exchangers are built from wet-etched, stacked, and
bonded 1.4571 stainless steel platelets. The multilamination micromixers contain either wet-etched, stacked, and
bonded 1.4571 stainless steel platelets or comb-shaped inlets with a diaphragm defining the mixing zone. The

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Fig. 3. On-line FT-IR studies of the Henry reaction performed in the modular microreaction system. FT- IR
Spectra of a mixture of 1.87m MeNO2 and 0.99m PhCHO in i-PrOH before the reaction (solid line) and in
equilibrium after 30 min of reaction time (broken line). Insert: Concentration of PhCHO (squares) and of 2-
nitro-1-phenylethanol (circles) vs. reaction time as measured by GC-FID (left axes, filled symbols). FT-IR
Absorbance (right axis, open squares) detected at 1702 cmÀ1 (CˆO stretching mode of PhCHO) vs. reaction
time.
temp.-controlled cap. reactor has electric heating and consists of a specially twisted (eight shaped) stainless steel
capillary. The cartridge reactor has an integrated temp.-controlled heating system and a removable cartridge for
easy and fast exchange of catalyst. The sealing plates consist of stainless steel with an FFKM O-ring for fluid-
tight connection. The delivery of the reaction solns. was performed by Knauer K-501 HPLC pumps equipped
with ceramic valves. For the heating and cooling of the thermal fluid, Thermo Haake DC30 and DC30-K20
thermostats were used. All starting materials were purchased from Aldrich and used without further
purification. GC Measurements were executed with a Thermo Finnigan Trace GC equipped with a Macherey &
Nagel Optima 5 cap. column (Æ0.25 mm, 0.25 mm, length 30 m). He was used as a carrying gas, eluted materials
were detected by a Thermo Finnigan flame-ionization detector (FID). The quantification of reaction yields was
performed using GC and alkanes as internal standards.
Synthesis of 2-Phenylethyl Acetate (Alkylation). The microreaction system consisted of three cross-flow
heat-exchangers, a stack-type micromixer, and a temp.-controlled cap. reactor. A soln. (50 ml) of Ac2O (1.46 ml,
15.4 mmol) in pyridine, and a soln. (50 ml) of 2-phenylethanol (900 ml, 5.52 mmol) and 4-(dimethylamino)pyr-
idine, (DMAP; 50 mg, 0.40 mmol) in pyridine were combined for a residence time of 15 min at 308, cooling to
208 after reaction. For GC analysis, the reactor eluent was collected into 1m HCl, extracted with Et2O, washed
with 5% Na2CO3, and dried (Na2SO4) to afford 2-phenylethyl acetate in 93% yield.
Synthesis of Benzyl Phenyl Ether (Williamson Ether synthesis). For both methods, the microreaction plant
consisted of three cross-flow heat-exchangers, a stack-type micromixer, and a temp.-controlled capillary reactor.
Method 1. A soln. (50 ml) of PhOH (1,85 g, 19.6 mmol), KOH (1,09 g, 19.5 mmol), and H2O (2 ml) in DMF
was combined with a soln. (50 ml) of PhCH2Br (1.20 ml, 10.1 mmol) in DMF, with a total residence time of
1 min at 508, cooling to 208 after reaction. For GC analysis, the reactor eluent was collected into 0.1m HCl,
extracted with Et2O, washed with 5% Na2CO3, and dried (Na2SO4) to afford benzyl phenyl ether in 100% yield.

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Method 2. A soln. (50 ml) of PhOH (1.852 g, 19.7 mmol) and KOH (1.245 g, 22.2 mmol) in H2O, and a soln.
(50 ml) of PhCH2Br (1.20 ml, 10.1 mmol) and Bu4NI (TBAI; 848 mg, 2.30 mmol) in CHCl3 were used; with a
residence time of 40 min at 508. For GC analysis, the reactor eluant collected into 0.1m HCl, extracted with
CHCl3, washed with H2O, and dried (Na2SO4) to afford benzyl phenyl ether in 87% yield.
Synthesis of 3a,4,7,7a-Tetrahydro-5,6-dimethylisobenzofuran-1,3-dione (Diels ± Alder Reaction). The
microreaction plant consisted of three cross-flow heat-exchangers, a stack-type micromixer, and a temp.-
controlled cap. reactor. A soln. (50 ml) of maleic anhydride (4.67 g, 48 mmol) in 1-methylpyrolidin-2-one
(NMP) and a soln. (50 ml) of 2,3-dimethylbuta-1,3-diene (8.1 g, 100 mmol) in NMP were combined and flowed
with a residence time of 30 min at 608, cooling to 208 after reaction. For GC analysis, the reactor eluant was
collected into CHCl3 and analyzed immediately to afford the title compound in 98% yield.
Synthesis of Ethyl Cinnamate.(ˆ Ethyl 3-Phenylprop-2-enoate). Method 1: Horner± Wadsworth ± Emmons
Reaction. The microreaction plant consisted of three cross-flow heat-exchangers, a stack-type micromixer, and a
temp.-controlled cap. reactor. A soln. (30 ml) of PhCHO (650 ml, 6.40 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-
5-ene (TBD; 898 mg, 6.45 mmol) in MeCN was combined with a soln. (30 ml) of triethyl phosphonoacetate
(1.228 g, 5.48 mmol) in MeCN, and flowed at 508 with a residence time of 10 min, cooling to 208 after reaction.
For GC analysis, the reactor eluant was collected into 10% NH4Cl soln., extracted with AcOEt, and dried
(Na2SO4) to afford the title compound in 91% yield.
Method 2: Heck Reaction. The microreaction plant consist of two cross-flow heat-exchangers, a stack-type
micromixer, and a temp.-controlled cartridge reactor. A soln. (50 ml) of ethyl acrylate (2.70 g, 26.9 mmol) in
NMP and a soln. (50 ml) of PhI (3.46 g, 16.9 mmol) and Et3N (1.69 g, 16,7 mmol) in NMP were flowed through a
solid-phase cartridge reactor loaded with 10% Pd on C (116 mg) at 1308 with a residence time of 30 min. For GC
analysis, the reactor eluant was collected in H2O, extracted with Et2O, and dried (Na2SO4) to afford the ethyl
cinnamate in 95% yield.
Synthesis of 2-Nitro-1-phenylethanol (Nitroaldol Addition, Henry Reaction). The microreaction plant
consisted of two cross-flow heat-exchangers, a stack-type micromixer, and a temp.-controlled cap. reactor. A
soln. (50 ml) of PhCHO (10.5 g, 99.3 mmol) and 11.4 g (186 mmol) MeNO2 in i-PrOH was combined with a soln.
(50 ml) of TBD (2.78 g, 20.0 mmol) in i-PrOH at 28, and flowed at 208 with a residence time of 10 min. For GC
analysis, the reactor eluant was collected into 10% NH4Cl soln., extracted with Et2O, and dried (Na2SO4) to
afford the title compound in 78% yield.
Synthesis of Benzylidene-acetone (ˆ4-Phenylbut-3-en-2-one) and Dibenzylidene-acetone (ˆ1,5-Diphenyl-
penta-1,4-dien-3-one) (Aldol Condensation). The microreaction plant consisted of three micromixers and a cap.
reactor. In the first micromixer, a soln. of 0.5m acetone in EtOH is mixed with a soln. of 0.25m PhCHO in EtOH.
Subsequently, the obtained mixture is mixed with a soln. of 1.5m KOH in EtOH and is allowed to pass through
the cap. reactor at 208. For GC analysis, the eluant was quenched by 50% AcOH and extracted by CH2Cl2 to
afford benzylidene-acetone in 59% yield and dibenzylidene-acetone, in 20% yield.
This research was supported by GlaxoSmithKline (Scholar Award to P.H.S.), the Alfred P. Sloan
Foundation (Fellowship to P.H.S.), and Merck (Academic Development Program Award to P.H.S.). Fruitful
cooperation with Dr. M. Adamczyk of Mettler Toledo GmbH concerning the FT-IR measurements is gratefully
acknowledged.
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Received September 13, 2004