Multistep microchemical synthesis enabled by microfluidic distillation

Article abstract of DOI:10.1002/anie.200904634

(Figure Presented) Microchemical solvent switch: A continuous-flow, multistep Heck synthesis was made possible by integrating microreactors, liquid-liquid extraction, and microfluidic distillation. The microfluidic distil-lation enabled solvent exchange from CH₂CI₂ in the first reaction step to N,Ndimethylformamide (DMF) in the final reaction step.

Full text of DOI:10.1002/anie.200904634

Angewandte
Chemie
DOI: 10.1002/anie.200904634
Microreactor Networks
Multistep Microchemical Synthesis Enabled by Microfluidic
Distillation**
Ryan L. Hartman, John R. Naber, Stephen L. Buchwald,* and Klavs F. Jensen*
Complex organic molecules, such as active pharmaceutical
ingredients, are synthesized by multiple reactions, which
require a workup and isolation of the intermediates. Recent
interest in microfluidic systems for continuous-flow synthesis
has motivated the integration of multiple chemical reactions
and separations in an attempt to streamline the process.[1–4]
Microreactor networks provide advantages for chemical
synthesis such as enhanced heat and mass-transfer character-
istics, safety of operation, isolation of sensitive reactions from
air or moisture, and a reduction of hazardous waste, while
potentially providing a fundamental understanding of how
production scale processes operate.[5–16] Nevertheless, studies
combining multiple steps in a flow system are relatively
limited.[1–3,17–25] Recently, multiple reaction steps were com-
bined with intermediate liquid–liquid extractions to provide a
continuous-flow synthesis of carbamates, which proceded via
a Curtius rearrangement of organic azides and subsequent
reaction of the isocyanate with an alcohol.[1] This example
illustrates the advantage of forming and immediately using
small quantities of potentially hazardous intermediates
(organic azides) in continuous flow systems. By taking
advantage of the high interfacial area in microscale multi-
phase flow systems, intermediate extraction steps allowed
completion of three sequential reaction steps.[1] Other reports
have combined reactions with a liquid–liquid extraction for
CoII wet analysis,[3] multiple reaction steps without inter-
mediate separations,[19,22] multiple steps with off-line workups
using reagents and catalysts on solid supports,[17,21] and solvent
exchange by evaporation through porous poly(dimethylsil-
oxane).[18] The integration of reactions with analysis on a chip
has also advanced the field of micro total analysis systems
(mTAS).[20,26,27] These studies underscore the importance of
integrating different unit operations to perform synthetic
transformations.
equally essential for continuous-flow chemistry, with single-
step liquid–liquid extraction[28–30] and microevapora-
tion[18,31–35] having already been demonstrated. Distillation is
an important method for separating liquid mixtures and can
allow both purification and solvent exchange. Distillation
processes operate by exploiting the difference in volatility
between the components in a liquid mixture. Microfluidic
distillation, based exclusively on boiling point differences, is
challenging because surface forces dominate over gravita-
tional forces at these micro-scale. By using gas–liquid
segmented flow in conjunction with gas–liquid separators,
limitations were overcome to enable the separation of binary
solvent mixtures.[36] Combining microfluidic distillation with
multiple reaction steps would offer a tool for synthetic organic
chemistry and would provide a deeper understanding of how
multistep microfluidic processes operate. In the current work,
we present the first example of a multistep chemical synthesis
employing a microfluidic distillation to exchange reaction
solvents (Figure 1).
The Heck reaction is a versatile tranformation in organic
chemistry[37,38] which finds applications in the production of
active pharmaceutical ingredients,[39] natural product syn-
thesis,[40,41] and fine chemical production.[42] In addition to aryl
halides, aryl triflates and nonaflates can be used as coupling
partners to extend the scope of the reaction to a wider range
of starting materials and to access regioisomeric products.[43]
A typical batch synthesis requires a variety of reactions,
separation techniques and purifications. Separations are
[*] R. L. Hartman, Prof. K. F. Jensen
Department of Chemical Engineering
Massachusetts Institute of Technology
77 Massachusetts Ave., Cambridge, MA 02139 (USA)
Fax: (+1)617-258-8992
E-mail: kfjensen@mit.edu
Homepage: http://web.mit.edu/jensenlab
J. R. Naber, Prof. S. L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Ave., Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] K.F.J. and S.L.B. thank the Novartis International AG for funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904634.
Figure 1. Reaction and separation scheme for continuous-flow synthe-
sis involving solvent switch using microfluidic distillation.
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Because of this, examples of Heck reactions with aryl triflates
toluene (or DMF) and aryl triflate. The liquid and vapor
phases were additioanlly separated by exploiting the differ-
ences in their surface tensions. The device was designed such
that the liquid (i.e., reaction products and solvent) flowed
through an integrated PTFE membrane (0.5 mm pore size)
whereas the vapor did not. Detailed pressure drop calcula-
tions, device fabrication, and theory of operation have been
previously reported.[36]
In addition to the multistep experiments, samples of the
aqueous phase, vapor condensate, and product streams were
collected after the distillation stage for analysis. A photo-
graph of a set of these samples is shown in Figure 1. It can be
seen in this Figure that the distillate appeared to be colorless
while the product stream was orange-brown in color. NMR
analysis confirmed that the triflate remained in the liquid
product stream in the case of dichloromethane-to-toluene
solvent exchange, and that the starting material was con-
verted into the triflate in 91–95% yield. The analysis also
identified that 93% of the DIEA was extracted into the
aqueous phase whereas the remaining 7% was in the liquid
product stream. The vapor condensate exiting the distillation
stage was exclusively comprised of CH2Cl2 and toluene as
confirmed by NMR analysis.
are common; however, the almost complete lack of commer-
cial availability of aryl triflates necessitates their preparation
prior to their use in Heck reactions.[44–48]
Triflates are commonly prepared, in chlorinated solvents,
from phenols and trifluoromethanesulfonic anhydride using
stoichiometric amine bases. After the reaction, a general
work-up procedure can include removal of the chlorinated
solvent and addition of another solvent such as ethyl acetate
(EA) to facilitate the workup. Further steps involve liquid–
liquid extraction of the reaction mixture sequentially with
aqueous acid, base, and brine to remove salt byproducts and
excess reagents, subsequent removal of the solvent, and often
purification of the triflate. In the second reaction step, the
purified triflate, alkene coupling partner, amine base, palla-
dium precatalyst and ligand are combined in a polar aprotic
solvent, such as DMF, and heated to 1008C or higher for the
duration of the reaction (Scheme 1).
When a liquid mixture is comprised of two or more
components with different volatilities, a phase equilibrium of
the varying compositions exists and can be represented by a
McCabe–Thiele diagram (see the Supporting Information for
more details).[52,53] Figure 2 shows the McCabe–Thiele dia-
gram for the CH2Cl2–toluene solvent exchange that was
studied. In Figure 2, the theoretical equilibrium of a CH2Cl2/
toluene binary mixture (at 70.08C) is shown by the curved
line. The solid straight lines are described by Equation S3 (see
the Supporting Information) and represent the mass balance
during the separation of CH2Cl2 and toluene for both triflate
syntheses. Details on how these operating lines were obtained
can be found in the Supporting Information section. For the
synthesis of (S)-1,1’-binapthyl-2,2’-diyl bis(trifluoromethane-
sulfonate) (binol triflate), we observed that CH2Cl2 compo-
Scheme 1. Model chemistry for continuous-flow solvent exchange. DIE-
A=diisopropylethylamine, Tf=trifluoromethanesulfonyl, dppp=1,3-
bis(diphenylphosphino)propane, DMF=N,N-dimethylformamide.
In the continuous-flow process, we wanted to take
advantage of both the glassware-like compatibility and
excellent heat transfer properties of silicon based micro-
reactors to perform the chemistry, and the high interfacial
area that results from micron length scales to increase the
efficiency of the liquid–liquid extraction.[28] The first reaction
step, the synthesis of an aryl triflate from a phenol and triflic
anhydride (see Scheme 1), was carried out in a microreacter
as illustrated in Figure 1. The syntheses of two different aryl
triflates were investigated at 208C: 4-tert-butylphenyl tri-
fluoromethanesulfonate and (S)-1,1’-binaphthyl-2,2’-diyl bis-
(trifluoromethanesulfonate). Upon exiting the microreactor,
the product was combined with 2.0m hydrochloric acid (HCl)
and segmented flow was established.[49–51] Side-by-side contact
of HCl slugs with the organic phase enhanced mass transport
of DIEA to the aqueous droplets, making possible a single-
stage liquid–liquid extraction.[1,28,49–51]
As shown in the reaction sequence of Figure 1, purified
aryl triflate exiting the liquid–liquid extraction was combined
with pure toluene (or DMF). The resulting stream (with a
dichloromethane-to-toluene volumetric ratio of 1:4) was then
delivered to the microfluidic distillation device (Figure 1).
Gas–liquid segmented flow was established by combining
nitrogen gas with the liquid stream, which enabled controlled
flashing. The temperature of the distillation device (708C)
was maintained above the boiling point of CH2Cl2 (i.e., 408C)
yet below the boiling point of toluene (i.e., 1108C) or DMF
(i.e., 1538C). Consequently, the vapor phase was enriched
with CH2Cl2 while the liquid phase was comprised mostly of
Figure 2. Mole fraction of CH2Cl2 in the liquid product (x) and vapor
condensate (y) streams for the separation of CH2Cl2/toluene at 708C.
900
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sitions of (0.11 Æ 0.01) [liquid product stream] and (0.41 Æ
In the final reaction step (see Scheme 1), a palladium-
0.01) [vapor condensate stream] were close to those predicted
catalyzed coupling of 4-tert-butylphenyl triflate with n-butyl
vinyl ether was carried out by combining the product stream
exiting the microfluidic distillation stage with the other
reagents and a catalyst in a downstream microreactor at
1258C (see Figure 1). Analysis of the samples exiting the
microreactor elucidated the extent of the reaction. Table 1
shows the residence time, CH2Cl2 composition, conversion of
aryl triflate, and yield of the Heck product with increasing
distillation stage temperature.
~
by the equilibrium diagram ( in Figure 2). Similarly, values
of (0.09 Æ 0.01) [liquid product stream] and (0.38 Æ 0.01)
[vapor condensate stream] were measured during the syn-
thesis and separation of 4-tert-butylphenyl triflate (& in
Figure 2). Careful analysis of Figure 2 also shows that the
CH2Cl2 content of the feed stream was reduced from 0.2 (or
0.25 for binol triflate) to 0.1 mol fraction. Therefore, diluting
the product stream from the first reaction step and carrying
out one distillation step resulted in a switch of the solvent
compostion from 100% CH2Cl2 to 90:10 toluene/CH2Cl2.
The synthesis of 4-tert-butylphenyl trifluoromethanesul-
fonate and subsequent solvent exchange from CH2Cl2 to
DMF was also investigated (Figure 3). We observed that
Table 1: Residence time (t), CH2Cl2 composition, conversion, and yield
as a function of distillation temperature.
T [8C]
t [min]
CH2Cl2
[vol%]
Conv. Æs.d.
Yield Æs.d.
[%][a]
[%][a]
110
120
125
5.1
5.5
8.1
9.6
7.1
6.0
47.1Æ8.7
67.6Æ4.5
96.3Æ0.4
42.8Æ5.9
57.5Æ4.1
76.8Æ0.7
[a] s.d.=standard deviation for three samples.
Increasing the temperature increases the amount of
volatile solvent separated from the product stream, which
decreased the volume fraction of CH2Cl2, increased the
concentration of the triflate, and decreased the flow rate of
the product stream. Concentrating the aryl triflate entering
the final reactor increased the reaction rate while decreasing
the total flow rate resulted in a longer residence time for the
reaction (Table 1). Batch experiments were performed to
elucidate the influence of residual CH2Cl2 on the Heck
reaction. Figure S1 in the Supporting Information shows that
the reaction was most efficient in pure DMF and increasing
the fraction of CH2Cl2 decreased the product yield, which was
in agreement with the results in flow. As shown in Scheme 1,
reduction of the triflate was also observed during the Heck
reaction. The selectivity for the Heck product relative to the
reduced product remained constant and was estimated to be
approximately 15:1.
Figure 3. Mole fraction of CH2Cl2 in the liquid product (x) and vapor
condensate (y) streams for the separation of CH2Cl2/DMF at 120 and
1258C. The curved dashed line represents the change in equilibrium.
The preparation of an aryl triflate and a subsequnet Heck
reaction of this triflate represented a case study for multistep
synthesis with integrated microfluidic distillation. Continuous
operation of the scheme presented in this paper could
produce uninterrupted quantities of 1-(1-butoxyvinyl)-4-tert-
butyl benzene. Based on data reported in Table 1 and the
residence times investigated, approximately 32 mghÀ1 (or
0.135 mmolhÀ1) of product could be synthesized. To test this,
an experiment was repeated using the conditions from line 3
of Table 1 and Table S1 (see the Supporting Information), and
the product stream was collected for 5.5 hours. As described
in the Supporting Information, the product was hydrolyzed to
the methyl ketone,[54] which was isolated in a 69% yield. Just
as importantly, the working principles can be applied to other
chemical reactions to achieve continuous-flow syntheses. For
example, toluene could be removed to concentrate the
isocyanate intermediated in the flow synthesis of carbamates
without the need for a collection/boiling tank.[1] In addition to
performing manipulations with solvents during a synthesis,
microfluidic distillation can potentially be used as a product
increasing the distillation temperature from 1208C to 1258C
resulted in a fundamental change in operation. At 1208C, the
slope of the operating line (i.e., the ratio of molar flow rate of
liquid stream to vapor condensate) was greater than one,
however, at 1258C the slope was less than one. Such control
over flow rates is advantageous for continuous-flow chemical
processes. Adjusting temperature alone can potentially
change the entire outcome of the downstream microchemical
process. Trace amounts of aryl triflate (< 0.3 mol%) were
found in the vapor condensate collected during solvent
exchange from CH2Cl2 to DMF, implying that operation at
higher temperatures resulted in product vaporization. Calcu-
lation of the total molar flow rates through the system
revealed that the mole fraction of aryl triflate vaporized, f,
ranged from 0.07 to 0.22. Loss of product in a chemical
process is undesirable, but can potentially be minimized using
a more selective separation process. For example, multistage
distillation would enable lower operating temperatures, max-
imizing solvent separation, and minimizing product losses.
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solution of Tf2O (1.2m) was loaded into a separate syringe (Hamilton
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Figure 1) using
a Harvard Apparatus syringe pump (3 to
4 mLminÀ1). Two additional pumps and five separate syringes were
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Keywords: Heck reaction · microfluidic distillation ·
microreactors · palladium · synthetic methods
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