Kinetic and scale-up investigations of epoxide aminolysis in microreactors at high temperatures and pressures

Article abstract of DOI:10.1021/op100252m

A continuous-flow microreactor is applied for a kinetic study of a model β-amino alcohol formation by epoxide aminolysis. A large number of experiments are performed in a short time with minimal reagent consumption. The kinetics of formation of secondary

Full text of DOI:10.1021/op100252m

Organic Process Research & Development 2011, 15, 131–139
Kinetic and Scale-Up Investigations of Epoxide Aminolysis in Microreactors at High
Temperatures and Pressures
Nikolay Zaborenko, Matthew W. Bedore, Timothy F. Jamison,* and Klavs F. Jensen*
Departments of Chemistry and Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts AVenue,
Cambridge, Massachusetts 02139, United States
Abstract:
ease of application. Elevating the reaction temperature is a
commonly accepted method of reaction acceleration, typically
limited principally by the stability of the reagents and/or the
product. To achieve high temperatures, either high-boiling
solvents are used, or the reaction is pressurized to increase the
boiling point of the solvent. However, solvent properties have
a very strong effect on the reaction rate;3 therefore, it would be
highly preferable to select an appropriate solvent based on its
reaction properties and to enable the reaction to be performed
at the highest temperature allowable by the stabilities of the
chemical species.
While some work has been done using calorimetry for
kinetic studies of epoxide aminolysis,4-6 few reports have been
published analyzing the kinetics and selectivities of this
transformation in different solvents or applying kinetic results
to process design.7 Additionally, while there have been studies
reporting the different kinetic parameters of primary and
secondary amines acting as nucleophiles in the epoxide
aminolysis,8-10 we are unaware of reports investigating the rate
of the ꢀ-amino alcohol product itself reacting with another
molecule of epoxide (“bisalkylation”), generally an undesired
process that decreases the yield of the overall desired reaction.
Microreactors for continuous-flow syntheses are becoming
increasingly more popular in both academia and the pharma-
ceutical industry,11-14 often used to more efficiently produce
biologically active materials.15 As compared to conventional
batch processes, microsystems enable rapid heat and mass
transfer, resulting in improved reaction profiles for more
accurate kinetic studies. In addition to safely enabling high
A continuous-flow microreactor is applied for a kinetic study
of a model ꢀ-amino alcohol formation by epoxide aminolysis.
A large number of experiments are performed in a short time
with minimal reagent consumption. The kinetics of formation
of secondary aminolysis between starting epoxide and
product are decoupled from the primary synthesis, con-
structing a complete model for desired product formation.
The activation energy for the formation of desired product
is observed to be higher than those for regioisomer formation
and for secondary aminolysis, indicating that increasing
temperature improves selectivity in addition to accelerating
the reaction. A set of optimized conditions is then selected
for best reaction performance, and the process is scaled up
to a 100-fold larger reactor volume with model predictions
in good agreement with measured process performance.
1. Introduction
The synthesis of ꢀ-amino alcohols is an important pursuit
in the pharmaceutical industry and in academic research. A
number of active pharmaceutical ingredients (APIs), including
Oxycontin, Coreg, and Toprol-XL, contain this moiety, while
quite a few others, such as Zyvox and Skelaxin, feature
oxazolidones that can be formed through ꢀ-amino alcohol
precursors. Frequently, the precursors to ꢀ-amino alcohols are
difficult to synthesize and/or very expensive; thus, being able
to perform this reaction as rapidly and efficiently as possible
with the highest possible yield is of great interest.
(3) Kravchenko, V. V.; Kostenko, L. I.; Popov, A. F.; Kotenko, A. A.;
Koblik, I. V. Ukr. Chem. J. 1990, 56 (2), 168–172.
(4) Vinnik, R. M.; Roznyatovsky, V. A. J. Therm. Anal. Calorim. 2003,
73, 807–817.
The ꢀ-amino alcohol functional group can be assembled by
a number of synthetic pathways, with the most commonly
reported among them being the ring-opening of epoxides with
amine nucleophiles.1 The epoxide functional group has long
been a versatile functional group, able to produce a variety of
compounds via different ring-opening reactions.2 While epoxide
aminolysis can, in most cases, be performed in the absence of
a catalyst, it generally proceeds slowly when performed at
typical temperatures of solvent reflux.
The use of elevated temperatures is one of the more general
means of ꢀ-amino alcohol formation by the opening of epoxides
with amines. Additionally, because of its inherent simplicity
and lack of additional reagents and materials, it remains the
preferred option for industrially practical syntheses due to the
(5) Vinnik, R. M.; Roznyatovsky, V. A. J. Therm. Anal. Calorim. 2003,
73, 819–826.
(6) Vinnik, R. M.; Roznyatovsky, V. A. J. Therm. Anal. Calorim. 2004,
75, 753–764.
(7) Sirovski, F.; Mulyashov, S.; Shvets, V. Chem. Eng. J. 2006, 117 (3),
197–203.
(8) Rogers, D. Z.; Bruice, T. C. J. Am. Chem. Soc. 1979, 101 (16), 4713–
4719.
(9) Sundaram, P. K.; Sharma, M. M. Bull. Chem. Soc. Jpn. 1969, 42 (11),
3141–3147.
(10) Trejbal, J.; Petrisko, M. React. Kinet. Catal. Lett. 2004, 82 (2), 339–
346.
(11) Jas, G.; Kirschning, A. Chem.-Eur. J. 2003, 9 (23), 5708–5723.
(12) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade,
D. T. Chem. ReV. 2007, 107 (6), 2300–2318.
(13) Wiles, C.; Watts, P. Expert Opin. Drug DiscoVery 2007, 2 (11), 1487–
1503.
* Authors to whom correspondence may be sent. E-mail: tfj@mit.edu; e-mail:
kfjensen@mit.edu.
(14) Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 2008 (10), 1655–1671.
(15) Roberge, D. M.; Zimmermann, B.; Rainone, F.; Gottsponer, M.;
Eyholzer, M.; Kockmann, N. Org. Process Res. DeV. 2008, 12 (5),
905–910.
(1) Bergmeier, S. C. Tetrahedron 2000, 56 (17), 2561–2576.
(2) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59 (4), 737–799.
10.1021/op100252m  2011 American Chemical Society
Published on Web 12/14/2010
Vol. 15, No. 1, 2011 / Organic Process Research & Development
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131

Scheme 1. Aminolysis of 1 with 2, including the bisalkylation reactions
temperatures and pressures not easily attainable in batch
chemistry while allowing for rapid reaction monitoring,12
microreactors are highly efficient in the use of reagents for
kinetic screening studies.16,17
desired product 3, the kinetics of the bisalkylation reaction
(aminolysis of 1 with product 3 to form side product 5) were
first investigated. The determined reaction rate law of bisalky-
lation was then applied to decouple the kinetics of the primary
reaction and to obtain the overall rate law of product 3
formation.
The knowledge imparted by the use of microreactors can
then be applied, in conjunction with chemical engineering
principles, to obtain efficient operating parameters on the
industrial scale.20 In this work, the kinetic model obtained in a
given temperature range using dilute reagent solutions was
extrapolated to higher temperatures and industrially relevant
concentrations to demonstrate whether it is applicable in a broad
range of conditions.
In our previous work,18 we have demonstrated highly
efficient aminolyses of epoxides using a continuous-flow silicon
microreactor. Excellent yields and conversions with simple
terminal epoxides were obtained at residence times under 5 min
in ethanol under high temperature (180-240 °C) and pressure.
Epoxide aminolysis in a continuous-flow microreactor was
performed on pharmaceutically relevant syntheses (reaction
steps towards metoprolol and indacaterol), accelerating the
reactions by factors of 30-60 over the conventionally per-
formed processes with similar product yields. The continuous-
flow microreactor was also capable of reaching temperatures
not easily attainable in typical batch processes, allowing for
higher reaction temperatures, and due to the elimination of
headspace, volatile amines and solvents could be used in the
reaction without affecting reactant concentrations, allowing for
kinetic studies.
2. Results and Discussion
2.1. Heat Transfer Analysis. The high thermal conductivity
of silicon (148 W/m ·K compared to stainless steel ∼40
W/m·K) greatly aids in spreading heat and significantly reduces
the occurrence of hot spots. In the heated reactor zone, the
compressed heating block, manufactured of aluminum and with
graphite as the liner between the block and the reactor (see
Experimental Section), further helped distribute the heat while
providing high heat transfer. A two-dimensional lengthwise
cross section of the reactor was simulated by finite element
analysis, including the heating and compression chucks. A
temperature of 455 K (182 °C) was assumed for the cartridge
heaters, and a temperature of 285 K (12 °C) was given for the
boundary between the compression piece and cooling fluid. The
overall results of the simulation are shown in Figure 1.
It can readily be seen that the etched-out area of the reactor
establishes thermal separation between the inlet/outlet area
(including the mixing zone) and the reaction area of the reactor.
This allows the area in contact with polymer o-rings and fittings
to remain at room temperature when the compression chuck is
water-cooled, while the reaction zone is at temperatures of up
to 300 °C. Additionally, the temperature at the location of the
To enable the determination of the optimal set of concentra-
tions and conditions for performing epoxide aminolysis, a
systematic evaluation of the kinetic parameters of the reaction
is necessary. The aminolysis of styrene oxide 1 with 2-ami-
noindan 2, as shown in Scheme 1, was selected for this study
because the reagents are electronically similar to those partici-
pating in the epoxide aminolysis step in the formation of the
pharmaceutical agent indacaterol.19 The kinetic evaluation was
performed using ethanol as the solvent, using very low
concentrations of reagents to enable the measurement of initial
reaction rates using short residence times and very low
conversions. To fully determine the rate of formation of the
(16) Goodell, J. R.; McMullen, J. P.; Zaborenko, N.; Maloney, J. R.; Ho,
C.-X.; Jensen, K. F.; Porco, J. A.; Beeler, A. B. J. Org. Chem. 2009,
74 (16), 6169–6180.
(17) Murphy, E. R.; Martinelli, J. R.; Zaborenko, N.; Buchwald, S. L.;
Jensen, K. F. Angew. Chem., Int. Ed. 2007, 46 (10), 1734–1737.
(18) Bedore, M. W.; Zaborenko, N.; Jensen, K. F.; Jamison, T. F. Org.
Process Res. DeV. 2010, 14 (2), 432–440.
(19) Lohse, O.; Vogel, C. Process For Preparing 5-[(R)-2-(5,6-Diethyl-
indian-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one Salt,
Useful As an Adrenoceptor Agonist. WO/2004/076422, 2004.
(20) Roberge, D. M.; Gottsponer, M.; Eyholzer, M.; Kockmann, N. Chem.
Today 2009, 27 (4), 8–11.
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Figure 1. Finite element modeling of heat transfer in the reactor setup.
thermocouple is within 0.02 °C of that of the cartridge heaters.
Furthermore, the maximum temperature variation across the
reactive zone of the microreactor is <0.5 °C (see Figure S1 of
Supporting Information). At the fastest flow rate used (360 µL/
min), the fluid entering the reactive zone comes to within 1 °C
of the desired temperature within 0.09 s, or 0.45% of the total
residence time (see section S2 of Supporting Information for
the derivation).
time or (1)/([Pr]) - (1)/([Pr]0) versus time for data obtained
with equivalent starting amounts of 1 and 3. The mass balances
of the sample analysis closed to within the aforementioned range
relative to both of the reagents (1 and 3). The amount of initial
regioisomer 4 remained unchanged (to the limit of our detection)
in all samples, indicating that the rate of aminolysis of 1 by
this amine is insignificant and can be disregarded in the overall
rate law estimation. Additionally, no peaks corresponding to 6
or 7 have been observed in screening studies.
2.2. Kinetic Evaluation of Bisalkylation. Reaction kinetics
were investigated and calculated on the basis of several
assumptions regarding mixing within the microreactor channel.
As flow within the microreactor was always very laminar (see
section 2.4 for the discussion and Table 3 for the range of
Reynolds numbers), no turbulence-driven macromixing could
occur. Thus, the only effects to be considered were mixing by
diffusion, axial dispersion, and Dean flow. On the basis of the
small channel width, it was calculated that mixing by diffusion
ensures that all incoming streams are fully mixed prior to
entering the heated reaction zone. Additionally, the range of
Pe´clet numbers in which the reactor was operated (also
discussed in section 2.4 and Table 3) was such that axial
dispersion could be considered negligible, justifying the as-
sumption of plug flow. Therefore, conversions obtained in this
study could be directly related to chemical kinetics, as the
microreactor design ensured that mixing effects are negligible.
The bisalkylation reaction was first investigated because it
could be decoupled from the first reaction step. Upon reacting
1 with 3, two product peaks were observed by HPLC,
corresponding to two diastereomers of 5 (resulting from using
a racemic mixture of 1). This was confirmed by performing an
experiment with an optically pure enantiomer of 1 and observing
only one bisalkylation peak. No major peak corresponding to
6 was observed, indicating good selectivity of the bisalkylation
towards regioisomer 5.
The initial rates of reaction were approximated by measuring
the amount of product produced at the 20-s residence time
(shown in Table 1), consistently showing a rate increase by a
factor near 2 for every doubling of either reagent concentration.
Additionally, the plot of Figure 2c fit well to a linear correlation.
Combined, these results indicate that, at the evaluated condi-
tions, the reaction is first order with respect to each of 1 and 3,
or following the rate law:
rBis ) rBis1 + rBis2 ) kBis1[SO][Pr] + kBis2[SO][Pr] )
(kBis1 + kBis2)[SO][Pr] (1)
where Pr is desired product 3 and kBis1 and kBis2 represent the
rate constants of bisalkylation to form the two diastereomers
of 5.
The Arrhenius dependence was performed by varying the
temperature between 140 and 180 °C, at a residence time of
60 s and concentrations of 1 and 3 of 0.05 M each. Figure 3
shows the temperature dependences of 5 formation as plots of
ln(kBis1) and ln(kBis2) vs 1/T. The Arrhenius parameters were
determined to be:
8.4(2.4 kJ/mol
kBis1 ) e(-2.66(0.65)-
kBis1,453K
)
(
(
)
RT
(7.5 ( 6.9) × 10-3 M-1 s-1 (2)
The order of the reaction of the formation of 5 from 1 and
3 was determined by analyzing the results of varying reagent
concentrations (Figure 2), as well as fitting all obtained data
points to a rate model of first order in each of 1 (referred to as
SO in the equations) and 3 (designated as Pr), plotting (1)/([SO]0
- [Pr]0)ln [(1 - ([Pr]0 - [SO]0)/([Pr]))(([Pr]0)/([SO]0))] versus
12.0(2.2 kJ/mol
kBis2 ) e(-1.89(0.62)-
kBis2,453K )
)
RT
(6.2 ( 5.3) × 10-3 M-1 s-1 (3)
The observed rate constant data showed good agreement with
the experimental results obtained in our previous work.18 The
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133

Figure 3. Arrhenius correlation between temperature and rate
constants of bisalkylation (0 and ∆: the two bisalkylation
diastereomer products).
us to account for the rate of consumption of 1 due to that
reaction in addition to the primary aminolysis. At the explored
conditions, the ratios of the two bisalkylation products were
nearly identical to the ratios obtained at the same temperature
during the bisalkylation kinetics investigation, and no quantifi-
able amounts of bisalkylation products 6 or 7 were observed
by HPLC. This indicates that the side product 4 does not
participate in the bisalkylation reaction to a significant extent,
thus allowing us to discount the consumption of 1 by that
reaction route.
The orders of the reaction of the formation of 3 and 4 from
1 and 2 were determined by analyzing the results of varying
the reagent concentrations (Figure 4), as well as fitting all
obtained data points to a rate model of first order in each of 1
and 2 (referred to as AI in the equations), plotting (1)/([AI]0
-[SO]0)ln [(1 +([AI]0 -[SO]0)/([SO]))(([SO]0)/([AI]0))] versus
time. On the basis of the above discussion, the sum total of the
bisalkylation products was attributed to the reaction of 3 with
1; thus, the produced concentrations of 5 were added to that of
3 for the calculation of the rate constants.
The initial rates of reaction were approximated by measuring
the amount of product produced at the 20-s residence time
(shown in Table 2), consistently showing a rate increase by a
factor near 2 for every doubling of either reagent concentration.
Additionally, the plot of Figure 4c fits very well to a linear
correlation. Combined, these results indicate that, at the evalu-
ated conditions, both bisalkylation reactions are first order each
with respect to 1 and 2, or following the rate law:
Figure 2. Bisalkylation reaction order determination through
evolution of concentrations of the two diastereomers of product
5 [(a)and (b)] (]: initial concentrations of 1 and of 3 of 0.025
M each; 0: initial concentration of 1 of 0.025 M and of 3 of
0.050 M; ∆: initial concentration of 1 of 0.025 M and of 3 of
0.10 M; O: initial concentrations of 1 and of 3 of 0.050 M each);
(c) plot of all reaction data points as a natural logarithm
function of concentration of 3 vs time.
Table 1. Initial reaction rates of formation of the two
diastereomers of 5 in the experiments in Figure 2 (a) and (b)
(right and left sections of cells, respectively), given as 10-6
mol L-1 s-1
ri ) ki[SO][AI]
(4)
concentration of 1
where ri represents the rate of formation of 3 (k1) or of 4 (k2).
Therefore, the rates of formation of the product 3 and of
consumptions of 1 and 2 are expressed as follows:
0.025 M
0.05 M
concentration of 3
0.025 M
0.050 M
0.10 M
6.37; 4.56
14.3; 10.9
32.4; 23.6
29.6; 23.6
rPr ) k1[SO][AI] - (kBis1 + kBis2)[SO][Pr]
(5)
confidence intervals in the above equations were determined
using the error propagation method21 (Supporting Information).
2.3. Kinetic Evaluation of Primary Aminolysis. Having
the information regarding the kinetics of bisalkylation enabled
(21) Young, H. D. Statistical Treatment of Experimental Data; McGraw-
Hill: New York, 1962.
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Figure 5. Arrhenius correlation between temperature and the
rate constants of 1 aminolysis (0: product 3; ∆: regioisomer
4).
The Arrhenius dependence was performed by varying the
temperature between 140 and 180 °C, at a residence time of
60 s and concentrations of 1 and 2 of 0.10 and 0.12 M,
respectively. Figure 5 shows the temperature dependences of 3
and 4 formation as plots of ln(k1) and ln(k2) vs 1/T. The
Arrhenius parameters were determined to be as follows, with
errors calculated by the error propagation method (Supporting
Information):
27.2(2.0 kJ/mol
k1 ) e(3.41(0.55)-
k1,453K
)
(
)
RT
(2.2 ( 1.7) × 10-2 M-1 s-1 (8)
16.2(1.8 kJ/mol
k2 ) e(-0.80(0.50)-
k2,453K
)
(
)
RT
(6.1 ( 4.2) × 10-3 M-1 s-1 (9)
As expected on the basis of the electron properties of the
amine nitrogen, which make it more reactive as a secondary
amine than as a primary amine,2 the activation energies of the
primary alkylation are higher than those of the bisalkylation.
However, the pre-exponential factors are much greater, as would
be expected on the basis of the steric effects. Overall, this
indicates that, while the bisalkylation is often much faster than
the first alkylation in similar reactions at lower temperatures,
the large disparity in activation energies leads to a much better
selectivity for the desired single alkylation at increased tem-
peratures. Additionally, the slightly higher activation energy
toward the desired product 3 as compared to that toward the
regioisomer 4 also leads to improved selectivity for the desired
product with increased temperature.
Figure 4. Aminolysis reaction order determination of (a)
product 3 and (b) regioisomer 4 by varying concentration (]:
initial concentrations of 1 and 2 of 0.10 and 0.12 M, respectively;
0: initial concentrations of 1 and 2 of 0.10 and 0.24 M,
respectively; ∆: initial concentrations of 1 and 2 of 0.10 and
0.48 M, respectively; O: initial concentrations of 1 and 2 of 0.20
and 0.24 M, respectively; ×: initial concentrations of 1 and 2
of 0.20 and 0.48 M, respectively); (c) plot of all reaction data
points as a natural logarithm function of concentration of 1 vs
time.
Table 2. Initial reaction rates of formation of 3 and 4 in the
experiments in Figure 4 a and b (right and left sections of
cells, respectively), given as 10-4 mol L-1 s-1
Additionally, the model can be used to provide a response
surface of product yield with varying parameters such as
reaction temperature, residence time, and concentrations and
stoichiometric ratios of reagents. An ordinary differential
equation solver on the rate expressions given in eqs 5-7 (along
with the algebraic eqs 2, 3, 8, and 9 describing the Arrhenius
dependences of the rate constants on temperature) was applied
to generate such a surface, with Figure 6 showing some of the
corresponding time-slice cross sections and demonstrating the
effects of the aforementioned parameters.
concentration of 1
0.10 M
0.20 M
concentration of 2
0.12 M
0.24 M
0.48 M
2.86; 8.67
5.85; 18.3
12.4; 20.1
11.0; 34.9
21.9; 66.5
rSO ) -(k1 + k2)[SO][AI] - (kBis1 + kBis2)[SO][Pr]
(6)
rAI ) -(k1 + k2)[SO][AI]
(7)
where kBis1 and kBis2 were defined and calculated in the previous
section.
Because the rate constant of formation of 3 has the strongest
dependence on temperature among the calculated rate constants,
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The utility of microreactors for kinetic studies was evident
in this study. The setup enabled, with a single preparation of
two reagent solutions, to scan up to 35 sets of conditions
(concentrations, temperatures, and residence times) with samples
in triplicate, generating over 100 data points within one 8-h
period. Additionally, this procedure minimizes reactant use and
waste, as only 0.5-2 g of each reagent was necessary for such
an experiment set, and of the total of 30 mL of reaction solution
(including solvent for concentration control), fully 10 mL was
used directly as HPLC samples.
2.4. Reaction Scale-Up. To demonstrate the applicability
of the microreactor-obtained kinetic knowledge, the derived
kinetic model for the aminolysis of 1 with 2 was applied to
scaled-up flow and concentrations of reagents, using a 12.5-
mL stainless-steel-tube reactor (see Experimental Section). The
increased production was intended to verify that the information
resulting from microscale experiments is applicable to mesoscale
systems, from which performance in macroscale plants can be
gauged more easily. Additionally, conditions were intentionally
selected to be outside the scope of the model derivation to
ascertain whether the model is consistent in a wider parameter
space.
A set of conditions was selected on the basis of the derived
kinetic model. As can be seen in Figure 6, the optimal yield
relative to the epoxide reagent is achieved at higher temperatures
and with larger excess of the amine reagent. Thus, the reaction
conditions were selected as follows. The concentration of 1 was
selected as 0.4 M to mimic the solubility limit for the indacaterol
precursor epoxide, as discussed in our prior work.18 The
concentration of 2 was selected as 1.2 M, or a factor of 3 of
the epoxide concentration. As any excess of similar amines is
recovered downstream in similar industrial processes, this is
feasible both economically and in the process setup.
Figure 6. Modeled yield of 3 with time: (a) starting concentra-
tions of 0.2 M 1 and 0.24 M 2; blue solid line: 220 °C; green
dashed line: 200 °C; red dotted line: 180 °C; black dot-dash
line: 160 °C; brown dot-dot-dash line: 140 °C; (b) at 180 °C
with varying initial concentrations of 1 and 2; blue solid line:
1.0 and 1.2 M, respectively; green dashed line: 0.40 and 1.2 M,
respectively; red dotted line: 0.40 and 0.48 M, respectively;
black dot-dash line: 0.20 and 0.24 M, respectively; brown
dot-dot-dash line: 0.10 and 0.24 M, respectively.
Using the conditions described above and the derived kinetic
model, 99% conversion of 1 is expected at 110 s, resulting in
76.0% ( 4.9% yield (see Supporting Information for error
propagation calculations). However, these values are obtained
assuming plug flow, which was reasonable in the microreactor.
Table 3 compares the key parameters of the micro- and
mesoreactors, including important nondimensional fluid dynam-
ics properties, which are discussed below.
the model shows that higher temperatures lead to an improved
overall yield in addition to a faster reaction. Indeed, we have
seen that to be the case in the reaction screening study.18
Additionally, the model shows that a higher excess of the amine
leads to a better yield relative to the epoxide. Because the amine
is often a much less expensive reagent and can also be recovered
after the reaction, on scale it may be desirable to perform this
reaction at very high excesses of amine to drive the highest
possible product yield. If a smaller excess of amine is used,
then there may be a maximum in the yield relative to time, as
there may be a point at which there is sufficient product and
epoxide in solution for the bisalkylation reaction to be faster
than the primary product formation. Therefore, if it is desirable
to use only a small excess of the amine, then it is important to
know when the yield maximum occurs and to stop the reaction
at that point, rather than proceeding to full conversion of the
epoxide, as this would only cause loss of product. This
underscores the significance of understanding the reaction
kinetics.
The axial dispersion Pe´clet number is calculated as follows:
uL
D
PeAx
)
(10)
with L being the length of the tube, u being the linear velocity,
and D being the dispersion coefficient, given by the following
equation:22
u2d2
192D
D ) D +
(11)
Table 3. Comparison of key properties of the micro- and mesoreactors
volume cross section length flow rate
(mL) (mm) (mL/min)
(mm2)
velocity
(mm/s)
Re
D (m2/s)
PeAx
De
yield (%)
microreactor
0.120 0.160 (square)
750 0.03-0.36 3.12 -37.5 0.9-10.8 9.8 × 10-6
-
600-100 0.16-2.4 59-6918
1.4 × 10-3
9.8 × 10-3
mesoreactor 12.5
7.1 (circular)
1760 6.24
14.6
27.8
2.6 4.2 78.0-78.2
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Figure 7. Cartoon of the effect of Dean flow in a curved cylindrical tube on two incoming sections of fluid; the bottom array
demonstrates the effect of increasing Dean number (from left to right). Adapted from Sudarsan and Ugaz.24
where D is the diffusion coefficient, u is the linear
velocity, and d is the equivalent diameter. A diffusion
coefficient D of 10-9 m2/s was used (while exact values
for the starting materials in ethanol were not available,
compounds similar in size and functional groups displayed
diffusivities of this scale23). The axial dispersion Pe´clet
number PeAx for the microreactor indicates little deviation
from plug flow. As the larger-scale reactor has a fairly
large inner diameter and as flow is fairly rapid, dispersion
is expected to play a large role. The first moment of
residence time distribution E was calculated on the basis
of the dispersion coefficient D calculated above. Because
the active reactor section is a length of channel that is
directly and seamlessly connected to identical channels
in the cooled reactor section at both the inlet and outlet,
entrance and exit effects can be neglected; thus, the reactor
channel can be treated as an ‘open-open’ vessel with axial
dispersion, to which the following relation applies:22
dispersion due to the parabolic flow profile. The Dean
number De is given as:
D
De ) Re·
(14)
ꢀ2R
where D is the inner diameter of the pipe and R is the
curvature radius. With the Schmidt number (using proper-
ties of pure ethanol) calculated to be 1500, the value of
De2Sc is 26500, in which regime the effective dispersion
is expected to be about 20% of the calculated value,25
making it more similar to plug flow. Thus, the expected
yield of 3 would be 75.4% ( 4.9%. Overall, the yields
with and without dispersion and Dean flow have overlap-
ping confidence intervals; thus, it is not expected to be
able to determine experimentally the effect of dispersion
on this system.
This reaction was performed by flowing a total of 163 mL
(13 residence volumes) of solution through the reactor, taking
a total of less than 30 min. Samples were taken at 3, 8, and 12
residence volumes. Each sample showed 100% conversion (no
significant amount of 1 was detected), and the yield of the
desired product 3 was between 78.0 and 78.2% (by HPLC,
nonisolated) for all three samples, which is within the confidence
intervals of the value predicted by the model. Overall, the
mesoscale setup reproducibly synthesized 9.2 g of desired
product 3 in 30 min, with a higher yield than previously reported
for this reaction.
2
u
Et )
e-(L - ut) /4Dt
(12)
√
4πDt
Conversion in a reactor with dispersion is given as:22
∞ XA,PFR(t)E(t) dt
0
(13)
j
Xout
)
∫
Performing this calculation on the kinetic model results
in a yield of the product 3 of 73.0% ( 4.7%, about 3.3%
lower than what is expected in a plug-flow reactor,
although the confidence intervals overlap with those of
yield without dispersion. Additionally, because it is a
curved tube, dispersion is expected to be reduced due to
Dean flow. In Dean flow, fluid is transported from the
inner to the outer wall due to the balance of forces on the
fluid caused by the curvature of the tube, as shown in
Figure 7, adapted from Sudarsan and Ugaz.24 This
transport of fluid across the cross section greatly increases
radial mixing, which acts to counter the effects of
3. Conclusion
The kinetics of epoxide aminolysis were investigated
at high temperatures and pressures, using styrene oxide 1
and 2-aminoindan 2 as the reagents. The bisalkylation
reactions between the desired product 3 and the epoxide
were investigated individually and decoupled from the
primary aminolysis kinetics. The overall reaction model
for the production of the desired product was obtained,
including the temperature dependence, suggesting per-
forming this reaction at the highest possible temperatures
with a large excess of the amine reagent to obtain optimal
yields. This study demonstrated the utility of microreactor-
(22) Levenspiel, O. Chemical Reaction Engineering, 3rd ed.; Wiley: New
York, 1999; p 32.
(23) Myint, S.; Daud, W.; Mohamad, A.; Kadhum, A. J. Am. Oil Chem.
Soc. 1996, 73 (5), 603–610.
(24) Sudarsan, A. P.; Ugaz, V. M. Proc. Natl. Acad. Sci. U.S.A. 2006, 103
(19), 7228–7233.
(25) Johnson, M.; Kamm, R. D. J. Fluid Mech. 1986, 172, 329–345.
Vol. 15, No. 1, 2011 / Organic Process Research & Development
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based flow systems for kinetic study to enable greater
understanding of a reaction and subsequent optimization
of the synthesis. A robust high-pressure, high-temperature
microreactor with very rapid thermal control enabled
highly efficient reaction and kinetics evaluations, greatly
reducing experiment preparation time relative to batch
screening and minimizing reagent consumption. A total
of less than 5 g each of styrene oxide 1 and 2-aminoindan
2 were necessary to perform a full multistep kinetic study,
with the ability to complete up to 35 reactions in a wide
range of concentrations, residence times, and temperatures
in a single workday with only a single preparation of two
reagent solutions per day. The determined kinetic param-
eters indicated that the activation energy of the formation
of the desired product 3 is higher than those for the
formation of regioisomers and for the bisalkylation
reactions. This results in the fortuitous effect that condi-
tions that lead to a faster reaction and higher conversion
(higher temperature) also improve reaction selectivity
towards the desired product. A scale-up of this reaction
was performed in a 12.5-mL steel tube mesoreactor, for
which dispersion was calculated and shown to have very
little effect. Synthesis of 9 g of desired product 3 was
achieved in 30 min, with 100% conversion and 78% yield
(by HPLC, nonisolated), in good agreement with predic-
tions from the kinetic models, thus applying attained
reaction understanding to gain significant improvement
in product yield over previously reported procedures.
stainless steel syringes. A third 8-mL syringe was filled
with pure ethanol. The reagent streams were pumped
through the microreactor at 250-psi backpressure at
different flow rates to attain desired concentrations of the
two reagents and reaction times. Temperature was varied
from 140 to 180 °C. In general, five microreactor volumes
(5 × 120 µL) were allowed to pass through the outlet
after each change in conditions to achieve steady state
before samples were taken for quantitative analysis. At
each set of conditions, samples were collected in tripli-
cate.
4.3. Microreactor Synthesis of 3. To perform the evalu-
ation of the bisalkylation kinetics, it was necessary to
synthesize 3, which was performed using the microreactor
system. Two syringes were loaded with 2 M 1 and 2.4 M
2, respectively, each in ethanol (resulting in 1 and 1.2 M
of 1 and 2, respectively, in the reactor). The solutions
were then flowed into the microreactor at 225 °C and 500
psi with a residence time of 4 min, and the outflow was
collected. Upon cooling to room temperature and solvent
evaporation, an off-white crystalline solid was formed.
1HNMR and HPLC confirmed it to be the desired product
3 with 97% purity (the balance was regioisomer 4). This
was deemed acceptable for the kinetic study and was used
without further purification.
4.4. Scaled-Up Synthesis Setup. The scale-up was per-
formed in a 6-ft-long (1.8 m), 316 stainless-steel smooth-bore
seamless tube, 1/4” o.d., 0.12” i.d. (3 mm) (McMaster,
89785K52), coiled at a 10-cm turn diameter, with 171 cm (12.5
mL) submerged in a 2-L bath of high-temperature silicone oil
200.50 (Hart Scientific, 5014). The reactor was connected on
both ends to 1/16” stainless-steel tubing by stainless-steel
reducing swaging unions (McMaster, 5182K242). At the outlet
end, 30 cm of narrow tubing connected the reactor to the 500-
psi backpressure regulator used previously, which flowed out
to a collection bottle. At the inlet end, 20 cm of narrow tubing
connected to the reactor a compression-packaged two-stream
silicon micromixer26 (see Supporting Information on micromixer
fabrication details). The two inlets of the micromixer were fed
by HPLC single-piston pumps (Rainin Dynamax SO-200). The
oil bath was placed on a stirplate with a 10-cm long magnetic
stirbar and stirred at 200 rpm. Heating was achieved by an
immersion heater controlled by a J-KEM Scientific two-channel
controller, monitored by a K-type thermocouple probe. The
outer walls of the oil bath were covered with 1”-thick fiberglass
rope for thermal insulation. The reaction was performed at 220
°C, at which temperature, placing another thermocouple at
different positions within the bath (including by the bath wall
vs center, at the bottom vs near the surface) showed a maximum
temperature difference of 0.2 °C. The two pumped solutions
were 1 (0.8 M) with 10 mol % naphthalene and 2 (2.4 M) to
result in a reaction stream of 1 and 2 at 0.4 and 1.2 M,
respectively.
4. Experimental Section
4.1. Microreactor Fabrication and Setup. The setup to
perform the kinetics determination was identical to that used
in our previous work.18 In brief, a silicon microreactor was
fabricated by deep reactive ion etching to form a square cross-
section channel (400 µm on the side), with a reactive volume
of 120 µL. The inlet and outlet section of the reactor was
compressed in an aluminum fluidic interface chuck with Kalrez
O-rings (Z1028 FFKM, size 005, Marco Rubber) and was
thermally isolated from the reactive area to allow it to be cooled.
A thermocouple was inserted into the heating interface of the
reactive zone at a depth 0.5 mm below the aluminum surface
in contact with the silicon device (with a 1-mm-thick graphite
liner between the aluminum and the silicon). To confirm the
thermal separation, finite element modeling was performed
(Comsol Multiphysics 3.2).
Inlet tubing was connected to three 8-mL high-pressure
stainless steel syringes (702267, Harvard Apparatus), which
were independently driven by three syringe pumps (PHD 2200,
Harvard Apparatus). The outlet tubing was connected to a
backpressure regulator, either 250 psi (U-608, Upchurch) or
500 psi (U-609, Upchurch). A standard PID controller (CN742,
Omega) was used to regulate temperature using two 35-W
cartridge heaters (CSS-01235/120 V, Omega). See Supporting
Information for heat transfer analysis.
4.5. Analytical. HPLC quantitative analysis was performed
on an Agilent 1200 series LC/MS using either an Eclipse XDB-
C18 or a Zorbax Eclipse Plus C18 reverse phase column, a
4.2. Microreactor Protocols for Epoxide Aminolysis
Kinetics. Two solutions in ethanol were prepared, one of
the desired epoxide (1 at 1 M or 3 at 0.25 M) with
napthlalene (internal standard, 10 mol %) and the other
of 2 (1.2 or 0.25 M), and placed in 8-mL high-pressure
(26) Zaborenko, N.; Murphy, E. R.; Kralj, J. G.; Jensen, K. F. Ind. Eng.
Chem. Res. 2010, 49 (9), 4132–4139.
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methanol/water mobile phase, and a 254- or 210-nm wavelength
detector. All reported yields were nonisolated, attained by HPLC
based on normalization of response factors using naphthalene
as an internal standard. Nearly all samples had mass balances
between 96% and 102%, which was judged acceptable on the
basis of HPLC variability. The small number of samples with
mass balances outside this range were not considered in the
kinetics evaluation.
for advice, in particular, Gerhard Penn, Berthold Schenkel, Oljan
Repic, Thierry Schlama, Mike Girgis, Lukas Padeste, and Felix
Kollmer.
Supporting Information Available
Heat transfer modeling and calculations of the microreactor;
layout and microfabrication of the micromixer; error propagation
derivations for kinetic rate constants and yield; dispersion
calculations of the steel mesoreactor. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment
This work was supported by the Novartis-MIT Center for
Continuous Manufacturing. We thank the members of this team
Received for review September 16, 2010.
OP100252M
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