Dibal-H reduction of methyl butyrate into butyraldehyde using microreactors

Article abstract of DOI:10.1021/op7002002

The reduction of methyl butyrate into butyraldehyde with Dibal-H in inicroreactors is described. Running the reaction continuously in a microreactor afforded results similar to those of batch experiments, but very low temperatures are not necessary and the reaction may be scaled-up without selectivity decrease. Different microreaetors were used, and their mixing performances were compared. Increasing the reaction concentration and thus the throughput showed that even when working with microreactors, heat management should not be underestimated. Multi-injection was tested as a way to better control the temperature at the mixing point(s).

Full text of DOI:10.1021/op7002002

Organic Process Research & Development 2008, 12, 163–167
Dibal-H Reduction of Methyl Butyrate into Butyraldehyde using Microreactors
Laurent Ducry* and Dominique M. Roberge*
Lonza Ltd., Valais Works, CH-3930 Visp, Switzerland
Abstract:
Scheme 1. Mechanism of the Dibal-H-mediated reduction
of methyl butyrate (1)
The reduction of methyl butyrate into butyraldehyde with Dibal-H
in microreactors is described. Running the reaction continuously
in a microreactor afforded results similar to those of batch
experiments, but very low temperatures are not necessary and the
reaction may be scaled-up without selectivity decrease. Different
microreactors were used, and their mixing performances were
compared. Increasing the reaction concentration and thus the
throughput showed that even when working with microreactors,
heat management should not be underestimated. Multi-injection
was tested as a way to better control the temperature at the mixing
point(s).
Table 1. Batchwise reduction of methyl butyrate (1) with
Dibal-H
butyraldehyde methyl butyrate
n-butanol
(4) [area %]
entry T [°C] (3) [area %]
(1) [area %]
Introduction
1
2
3
4
5
6
-65
-55
-35
-15
5
83
63
30
21
16
2
<1
10
28
40
49
53
17
27
42
39
35
45
The availability of simple methods to synthesize
aldehydes is of considerable interest to process chemists.
Although Lonza produces kilo- up to ton-scale quantities
of various aldehydes via ozonolysis of olefins, we decided
to further broaden our technology platform by improving
our control over the reduction of carboxylic esters into
aldehydes. With most reducing agents, the reduction of
carboxylic esters gives the primary alcohol and not the
corresponding aldehyde. Complete reduction up to the
alcohol followed by reoxidation to the aldehyde, for
example, via Swern oxidation, is thus often carried out,
for example, in total synthesis. As alternative to this
lengthy procedure, the partial reduction of carboxylic
20
at -65 and -55 °C, butyraldehyde (3) is formed as the major
product, at higher temperatures a mixture consisting mainly of
starting material 1 and alcohol 4 was obtained (Table 1).
Not to mention the extra cost associated with low
temperature, the industrial application of this approach is
limited by the exothermicity of the reaction. In the methyl
butyrate (1) reduction, ca. 240 kJ/mol is released according
to RC1 measurements in a Mettler Toledo calorimeter.
Thus, for isothermal operation, the Dibal-H addition time
increases with the scale of the reaction. As a consequence
of the limited half-life of the intermediate 2 (even at -78
1
esters with Dibal-H, has been reported for some time. In
this case, the intermediate formed by addition of the metal
hydride to the ester may be sufficiently stable so that no
significant amount of aldehyde is released before the
aqueous workup. Under conditions where the rate constant
°
C) and of the extended dosage times associated with the
k
1
is larger than k
reaction. Thus, little or no alcohol can be formed even if
is larger than k , which is generally the case since the
2
, little aldehyde is present during the
scale-up, this reaction can hardly be used batchwise on
an industrial scale. Indeed, even with precooling of the
Dibal-H solution, the addition time becomes long enough
in 630 L vessels that a considerable quantity of aldehyde
is released before the end of the reaction. This results not
only in alcohol formation but also in Dibal-H consump-
tion. For the reduction of another ester, ca. 95 area % of
the corresponding aldehyde was achieved on laboratory
scale at -78 °C, whereas on pilot scale only ca. 80 area
k
3
1
carbonyl group of aldehydes is more reactive than that of
esters.
Although some additives were reported to give improved
2
results, hardly any simple and general procedure applicable to
all esters is available as yet. A further limitation is the very
low temperatures required to stabilize the organo-aluminium
intermediate (2) and to obtain the desired partial reduction. This
is well exemplified by the Dibal-H reduction of methyl butyrate
%
purity was obtained at the same temperature. Running
such a reaction in a continuous fashion could be an
interesting alternative to circumvent this problem, but the
reaction exothermicity (vide supra), combined with its
rapid rate, requires good mixing properties and high heat
transfer performance. Recently, microreactor technology
has emerged as an attractive synthetic tool to handle such
(1), which we studied as a model reaction (Scheme 1). Whereas
*
To whom correspondence should be addressed. E-Mail: laurent.ducry@
lonza.com; droberge@uottawa.ca.
(
(
1) Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 619–620.
2) Muraki, M.; Mukaiyama, T. Chem. Lett. 1975, 215–218. Cha, J. S.;
Kwon, S. S. J. Org. Chem. 1987, 52, 5486–5487.
1
0.1021/op7002002 CCC: $40.75

2008 American Chemical Society
Vol. 12, No. 2, 2008 / Organic Process Research & Development
•
163
Published on Web 01/12/2008

Table 2. Dibal-H reduction of methyl butyrate (1) in the
although significant differences among microreactors exist. At
20 °C and above, the Dibal-H reduction of 1 is very fast (half-
Corning-HP microreactor using piston pumps
-
5
butyraldehyde methyl butyrate
n-butanol
(4) [area %]
life below 1 s, type A reaction), and is predominantly controlled
entry T [°C] (3) [area %]
(1) [area %]
6
by the mixing process. This reaction can thus be used to
1
2
3
4
5
-60
-50
-40
-20
5
86
88
82
63
14
1
1
13
11
17
20
35
compare the performance of various microreactors. Surprisingly,
early experiments afforded very similar results, regardless of
the microreactor type or the flow rate. This observation made
us realize that the pulsation of the piston pumps was limiting
the mixing quality. Our initial laboratory system was assembled
with Ismatec valveless piston pumps having pulsation frequen-
cies in the range of 200–1800 rpm. This pulsation proved to
be the dominant quality factor, masking the different mixing
properties of the various microreactors tested (Figure 1). It is
worth mentioning that a number of commercially available
microreactor systems still use this type of dosage pump. At -20
1
17
51
3
continuous reactions. Thereafter, we report our results
obtained in the Dibal-H-mediated reduction of ester 1
using different microreactors.
Results and Discussion
°C, the Corning-HP microreactor afforded 63 area % of
Initially, a 2.3% methyl butyrate (1) solution in toluene
butyraldehyde (3) with piston pumps (Table 2, entry 4) and 71
area % with mass flow controllers (Table 3, entry 12). For
passive-mixing microreactors, it is thus critical to use a pump
system without pulsation. The reactions described thereafter
were all carried out with thermal mass flow controllers from
Brooks, allowing pulsation-free operation of the microreactors.
Two types of microstructured reactors with contrasting
mixing principles were compared. The Ehrfeld cryo reactor is
(
feed 1) and a commercially available 20% Dibal-H
solution in toluene (feed 2) were precooled and continu-
ously pumped through the Corning-HP microreactor using
piston pumps. A total flow rate of 11–12 g/min with a
6
/1 split (corresponding to ca. 1.0 equiv of reducing agent)
was used. As in the batch systems, the temperature was found
to play a key role, with the decrease in selectivity occurring
at higher temperatures. Over 80% butyraldehyde (3) was
obtained at temperatures up to -40 °C (Table 2). The
aldehyde 3 was still the major product at -20 °C, whereas
in batch a temperature as low as -55 °C was necessary to
obtain a similar result (Figure 1). The ability to selectively
perform the partial reduction of esters at higher temperatures
presents a clear economical advantage.
7
a stainless steel microreactor with multi lamination mixing.
Its theoretical mixing time (t) depends on the width of the
laminar sheets (d) and the diffusion coefficient (D) according
to eq 1. The fluid lamellae are generated from the width (d) of
the laminar sheet. Two different sheets were used, one with 25
µm opening (ER-25), and one with 50 µm openings (ER-50).
2
d
t )
(1)
D
The Corning microreactors, made of glass, have a
mixing principle based on a chaotic flow regime in the
8
mixing zone. Two such microreactors were used, namely,
the Corning-LP and the Corning-HP, the later having the
same geometry but smaller channels (larger internal
structures) resulting in a higher pressure drop (HP) in the
mixing zone.
The Ehrfeld microreactor has an integrated cooling
system designed for carrying out reactions at low tem-
peratures. The ER-25 afforded close to 90% selectivity
in favor of the target aldehyde 3 at -55 °C (Table 3, entry
Figure 1. Selectivity as a function of temperature for batch
experiments (Table 1, entries 1–6) versus experiments with the
Corning-HP microreactor (Table 2, entries 1–5 and Table 3,
entries 12–14).
1
). As expected, the selectivity decreased with increasing
temperatures, but at significantly higher temperatures than
batchwise or with the Corning-HP used under pulsating
conditions. The ER-50 and the Corning-HP followed the
As a result of their tiny dimensions, most microreactors have
laminar flow regimes with low Reynolds numbers, depending
on the microreactor size and flow rate. Good mixing properties
(
(
5) Roberge, D. M.; Ducry, L.; Bieler, N.; Cretton, P.; Zimmermann, B.
Chem. Eng. Technol. 2005, 28, 318–323.
4
are actually one of the main advantages of microreactors,
6) For a review of the mixing influence, see: Bourne, J. R. Org. Process.
Res. DeV. 2003, 7, 471–508. For a review of microreactor mixing
principles, see: Hessel, V.; Löwe, H.; Schönfeld, F. Chem. Eng. Sci.
2005, 60, 2479–2501.
(
3) Ehrfeld, W.; Essel, V.; Löwe, H. Microreactors; Wiley-VCH: Wein-
heim, 2000. Fletcher, P. D. I.; Haswell, S. J.; Pombo-Villar, E.;
Warrington, B. H.; Watts, P.; Wong, S. Y. F.; Zhang, X. Tetrahedron
(7) Ehrfeld, W.; Golbig, K. G.; Hessel, V.; Löwe, H.; Richter, T. Ind.
Eng. Chem. Res. 1999, 38, 1075–1082.
2
002, 58, 4735–4757. Schwalbe, T.; Autze, V.; Wille, G. Chimia 2002,
5
6, 636–646. Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Angew.
(8) Corning Inc. Woehl, P.; Themont, J.-P. PCT publication WO 2005/
120690 A1. Corning Inc. Barthe, P. J.; Bieler, N.; Guermeur, C. C.;
Lobet, O.; Moreno, M.; Roberge, D.; Woehl, P. U.S. 2007/ 0264170
A1.
Chem., Int. Ed. 2004, 116, 410–451.
(
4) Roberge, D. M.; Bieler, N.; Thalmann, M. PharmaChem 2006, June,
1
4–17.
1
64
•
Vol. 12, No. 2, 2008 / Organic Process Research & Development

Table 3. Dibal-H reduction of methyl butyrate (1) in various microreactors using mass flow controllers
flow rate
[g/min]
feed 1
concn [%]
pressure
drop [mbar]
butyraldehyde
(3) [area %]
methyl butyrate
(1) [area %]
n-butanol
(4) [area %]
entry
microreactor
T [°C]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
ER-25
-55
-40
-20
0
12
12
12
12
12
12
12
12
12
10
10
12
12
12
20
12
20
2.3
2.3
2.3
2.3
2.3
2.3
2.3
1.2
2.3
3.5
5.0
2.3
2.3
2.3
2.3
2.3
2.3
1160
830
635
520
510
640
550
500
480
420
400
500
380
300
690
45
89
85
82
69
37
77
59
36
27
19
13
71
47
25
34
8
<1
<1
<1
9
32
2
15
28
35
42
45
1
21
37
28
60
53
11
15
18
22
31
21
26
36
38
39
42
28
31
38
37
33
29
ER-25
ER-25
ER-25
ER-25
20
ER-50
-20
ER-50
0
ER-50
20
ER-50
20
0
1
2
3
4
5
6
7
ER-50
20
ER-50
20
Corning-HP
Corning-HP
Corning-HP
Corning-HP
Corning-LP
Corning-LP
-20
0
20
20
20
20
110
19
same trend as the ER-25 but with lower yields at
comparable temperatures (Figure 2).
affords faster and better mixing and thus better selectivity
but also results in a significant increase in pressure drop
(Table 3, entries 14–17). The selectivity was actually
found to correlate with the logarithm of the pressure drop
(Figure 3). For this microreactor, the mixing is not
determined by the lamellae size since, even at low
Reynold’s number, the flow regime demonstrates chaotic
Although better selectivities are obtained at low tem-
perature, working at 20 °C where the reduction is very
fast maximizes the effect of the mixing (mixing controlled
conditions) and allows better comparison of the mixing
properties of these two types of microreactors. At a flow
rate of 12 g/min, better results were obtained with the
ER-25 than with the ER-50 and the Corning-HP, which
were themselves better than the Corning-LP (Table 3,
entries 5, 9, 14, and 16). For the Ehrfeld microreactor, a
significant gain in yield is obtained with a very slight
increase of pressure drop (Table 3, entries 5 and 9). This
is explained by eq 1 where the mixing time is a square
function of the width of the laminar sheets (d). For multi
lamination mixing, small dimensions of 25 µm fluid
lamellae allow significant gain in mixing quality with
limited increase of pressure drop when compared to 50
µm fluid lamellae. As a consequence of the small channel
size, however, the ER-25 and ER-50 reactors were prone
to fouling and plugging. This also led to significant result
variances when operated for longer period of time, making
these reactors impracticable for commercial applications
in the context of this reaction. The situation is different
for the Corning microreactors, where a higher flow rate
9
behavior. In fact, the main parameter influencing the
micromixing is the amount of energy per volume that is
introduced in the mixing zone (watt/liter). This situation
6
is comparable to turbulent flow regimes. Physically, this
energy ratio translates into pressure drop, a parameter that
is easily measured. The increase in pressure drop can be
generated by larger internal structures creating smaller
channels (see Corning-HP vs Corning-LP) or by higher
flow rates.
These observations are valid as long as the thermal
effect remains negligible compared to the mixing effect,
that is to say as long as the reaction mixture is highly
diluted (2.3% of ester 1 in feed 1, corresponding to an
adiabatic temperature rise of ca. 28 °C). Higher feed
concentrations afforded poorer selectivities (Table 3,
entries 8–11). This is the result of two phenomena working
in parallel. At higher concentrations the reaction rate is
increased, increasing further the mixing requirements. In
Figure 2. Selectivity as a function of temperature for various
microreactors (Table 3, entries 1–7, 9, 12–14).
Figure 3. Selectivity versus pressure drop at 20 °C (Table 3,
entries 5, 9, 14–17).
Vol. 12, No. 2, 2008 / Organic Process Research & Development
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Table 4. Dibal-H reduction of methyl butyrate (1) in the Corning multi-injection microreactor
injection
points
flow rate
[g/min]
feed 1
concn [%]
butyraldehyde
(3) [area %]
methyl butyrate
(1) [area %]
n-butanol
(4) [area %]
entry
T [°C]
1
2
3
4
5
6
7
8
9
20
20
20
0
1
1
1
1
1
1
1
2
3
4
4
4
11
17
23
11
17
23
26
26
26
26
37
43
2.3
2.3
13
17
21
27
39
43
17
22
24
24
24
23
62
59
56
52
44
42
56
53
52
52
52
53
25
24
23
22
16
15
25
25
24
24
25
24
2.3
2.3
0
2.3
0
2.3
0
10.0
10.0
10.0
10.0
10.0
10.0
0
0
1
1
1
0
1
2
0
0
0
addition, higher local temperature rises (hot spots) are
associated with increased concentrations. Even if the
influence of the mixing and of the heat management cannot
be fully separated, the lower reaction selectivity at high
concentration shows that the ER-50 microreactor does not
allow sufficient temperature control for this reaction.
Despite more efficient heat exchange than in batch
reactors, very fast and exothermic reactions carried out
in microreactors are not isothermal.
one to two injection points than to three or four. Upon
further increasing the flow rate to 37 and 43 g/min., the
selectivity did not vary (Table 4, entries 11 and 12). The
improved mixing at higher flow rate is presumably
compensated by the more severe hot spots.
Conclusion
The good selectivities obtained batchwise at -78 °C
in the Dibal-H reduction of carboxylic esters can be
reproduced in microreactors, with the advantage that a
continuous microreactor process can be effectively scaled-
up without selectivity decrease. The good mixing of
microreactors allows good selectivities at temperatures as
high as -20 °C. However, better mixing compared to a
batch process also means that the exothermicity of the
reaction is concentrated in a tiny zone, resulting in a local
hot spot. This local thermal effect can be split and thus
reduced by using the multi-injection concept. The use of
these microreactors should find broad application in the
fine chemical and pharmaceutical industry for reaction
sensitive to both temperature and mixing.
To have a better control of the reaction temperature, a
new type of microreactor where one of the feeds is first
split and then mixed with the second feed at various
injection points was developed by a joint collaboration
1
0
between Corning and Lonza. This microreactor has very
similar mixing design and the same channel sizes as the
Corning-HP reactor. It was tested in the context of the
methyl butyrate (1) reduction, using 1.0 equiv of Dibal-H
solution as previously. In the first experiments, only one
injection point was used to test the mixing properties of
the multi-injection microreactor and to compare it with
the reactors used previously at the same ester concentration
of 2.3 wt %. As expected, the multi-injection microreactor
gave results similar to those using the Corning-LP
microreactor at 20 °C (Table 4, entries 1–3). A better
mixing was obtained upon increasing the flow rate (more
energy in the mixing zone). The selectivity of the ER-25
and ER-50 reactors was nevertheless not achieved, since
the Corning microreactor was designed to operate at higher
flow rates in the range of 80 g/min.10 Logically, higher
proportions of the target aldehyde 3 were obtained when
lowering the reaction temperature to 0 °C (Table 4, entries
Experimental Section
Reaction Analysis. The reaction mixtures were analyzed
by GC with a HP-1 column. All samples were injected at
2
00 °C, and the column was heated from 40 to 280 °C
4
–6 or Figure 4). Upon increasing the concentration of
the methyl butyrate (1) solution from 2.3% to 10.0% (feed
) and with a 26 g/min flow rate, only 18 area % of
1
butyraldehyde (3) was formed as the consequence of
temperature rise at the mixing point (Table 4, entry 7).
Splitting the Dibal-H feed and injecting it at several
locations afforded better selectivities (Table 4, entries
8
–10). The influence is more important when going from
(
9) Schüter, M.; Hoffmann, M.; Räbiger, N. Chem. Ing. Tech. 2004, 76,
1
682–1688.
Figure 4. Influence of the flow rate on the formation of
butyraldehyde (3) in the Corning multi-injection reactor using
only one injection point (Table 4, entries 1–6).
(
10) Roberge, D. M.; Bieler, N.; Mathier, M.; Eyholzer, M.; Zimmerman,
B.; Barthe, P.; Guermeur, C.; Lobet, O.; Moreno, M.; Woehl, P.
Submitted to Chem. Eng. Technol.
1
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Vol. 12, No. 2, 2008 / Organic Process Research & Development

with a rate of 30 K/min. A FID detector was used at 280
added into a 2 M aqueous hydrochloric acid solution at
20 °C. Parameters such as total flow rate, concentration,
temperature, and pump type were varied throughout this
work as depicted in Tables 2-4. Corning and Ehrfeld
microreactors were used, and their respective character-
istics are described in the main text.
°
C (oven temperature).
Batch Reactions. All experiments were carried out in a
5
00 mL jacketed vessel equipped with a mechanical stirrer.
A 20% Dibal-H solution in toluene (1.0 equiv) was added
over 20 min to a 2.3% methyl butyrate solution in toluene
at the temperature indicated in Table 1. The reaction
mixture was then directly poured into a 2 M aqueous
hydrochloric acid solution at 20 °C. The organic phase
was analyzed by GC.
Acknowledgment
We thank our colleagues in the Corning and Lonza microre-
actor teams.
Continuous Reactions. The reactions were performed
with two feeds, namely, the methyl butyrate feed (1.2%
to 10.0% solutions in toluene) and the Dibal-H feed (20%
solution in toluene). The Dibal-H stoichiometry was kept
at 1.0 equiv throughout this work, corresponding to flow
rates of 10.3 g/min (ester) and 1.6 g/min (Dibal-H) or a
total flow rate of 11.9 g/min, for a 2.3% methyl butyrate
feed. The solution at the microreactor outlet was directly
Supporting Information Available
Structure of the Ehrfeld and Corning mixers. This material
is available free of charge via the Internet at http://pubs.acs.org.
Received for review September 5, 2007.
OP7002002
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