pubs.acs.org/joc
is especially problematic, as researchers often adjust the
Magnetically Driven Agitation in a Tube Mixer
Affords Clog-Resistant Fast Mixing Independent
of Linear Velocity
residence time of reagents within a reaction zone by changing
reagent flow rates, a change that also alters mixing behavior.
The advantage of these microchannel-based systems over
3
batch continues to be a controversial subject. Furthermore,
these systems are prone to clogging even when using see-
mingly homogeneous solutions, and require >1 s for com-
,
Sarah J. Dolman,* Jason L. Nyrop, and
†
‡
†
Jeffrey T. Kuethe
4
plete diffusive mixing in nonturbulent flow. While the issue
†
Department of Process Research, Merck Research
‡
of clogging can sometimes be addressed through dilution,
this approach results in both longer processing times and
greater solvent volumes, a negative impact on the product
Laboratories and Chemical Process Development &
Commercialization, Merck Manufacturing Division,
Merck & Co., Inc., P.O. Box 2000, Rahway,
New Jersey 07065, United States
5
mass intensity and environmental impact of the process. To
support the overarching goal of rapid scale up of continuous
processes, with minimal development efforts, we desired a
more suitable format for small-scale experimentation (<1 g
of starting material).
Received November 15, 2010
FIGURE 1. Magnetically driven agitation in a tube (MDAT)
mixer.
We sought a simple mixer for small-scale screening that
would afford fast mixing independent of flow rate, yet resist
clogging. Inspired by early HPLC solvent mixing work that
An economical and simple flow mixer based on magne-
tically driven agitation in a tube (MDAT) is reported.
Mixing via MDAT compared favorably to both Tee and
multilaminar mixers at low flow and was successfully
used to screen and optimize two challenging organome-
tallic reactions at low temperature without clogging or the
need for high dilution.
6
utilized agitation via magnets in stainless-steel tubing, we
placed two small magnets inside an empty HPLC column,
which was connected to a Tee mixer (500 μm). Placement of
this tube over a magnetic stir-plate afforded the magnetically
driven agitation in a tube (MDAT) apparatus illustrated in
Figure 1. Characterization of the mixing time in the MDAT
mixer was accomplished via the fourth Bourne competition
7
reaction (Scheme 1), an experimental protocol that com-
Flow chemistry has been a topic of considerable recent
1
interest with many reports of the utility of microchannel
pares the rate of acid-catalyzed hydrolysis of 2,2-dimethox-
ypropane (DMP) to methanol vs neutralization of NaOH
with HCl. If the mixing time is faster than the reaction time,
minimal methanol is produced, as the rate constant
mixers. The degree of mixing afforded by such mixers is
highly dependent on the linear velocity of the fluid through
the reactor, with fast mixing being observed only at the
8
3
2
for neutralization (k = 1.4 Â 10 (m /mol)/s) is several
1
highest flow rates. This dependence of mixing on flow rate
orders of magnitude greater than that for hydrolysis (k =
2
3
.6 (m /mol)/s). We compared three different mixers: (1)
8,9
0
(
1) Some recent publications include: (a) Illg, T.; Lob, P.; Hessel, V.
a multilaminar mixer (possessing 50 μm channels (Institut
f u€ r Mikrotechnik Mainz, GmbH), (2) a 500 μm Tee mixer
Bioorg. Med. Chem. 2010, 18, 3707. (b) Ye, X.; Johnson, M. D.; Diao, T.;
Yates, M. H.; Stahl, S. S. Green Chem. 2010, 12, 1180. (c) Kockmann, N.;
Gottsponer, M.; Zimmerman, B.; Roberge, D. Chem.;Eur. J. 2008, 14,
7
470. (d) Bogdan, A. R.; Poe, S. L.; Kubis, D. C.; Broadwater, S. J.;
McQuade, D. T. Angew. Chem., Int. Ed. 2009, 48 (45), 8547. (e) Baxendale,
I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed. 2009,
(3) Valera, F. E.; Quaranta, M.; Moran, A.; Blacker, J.; Armstrong, A.;
Cabral, J. T.; Blackmond, D. G. Angew. Chem., Int. Ed. 2010, 49, 2478.
(4) Falk, L.; Commenge, J. M. Chem. Eng. Sci. 2009, 65, 405.
(5) (a) Chin, P.; Barney, W. S.; Pindzola, B. A. Curr. Opin. Drug Discovery
Dev. 2009, 12 (6), 848. (b) Hessel, V. Chem. Eng. Technol. 2009, 32 (11), 1655.
(6) Gugger, R. E.; Mozersky, S. M. Anal. Chem. 1973, 45 (8), 1575.
(7) (a) Bladyga, J.; Bourne, J. R. Turbulent Mixing and Chemical Reac-
tion; John Wiley & Sons: New York, 1999. (b) Bladyga, J.; Bourne, J. R.;
Walker, B. Can. J. Chem. Eng. 1998, 76, 641.
4
(
8 (22), 4017. (f) Odedra, A.; Seeberger, A. Angew. Chem., Int. Ed. 2009, 48
15), 2699. (g) Gross, T. D.; Chou, S.; Bonneville, D.; Gross, R. S.; Wang, P.;
Campopiano, O.; Ouellette, M. A.; Zook, S. E.; Reddy, J. P.; Moree, W. J.;
Jovic, F.; Chopade, S. Org. Process. Res. Dev. 2008, 12 (5), 929. (h) Carter,
C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.;
Gaunt, N. L. Org. Process. Res. Dev. 2010, 14 (2), 393.
(2) (a) Yoshida, J.-I. Flash Chemistry; John Wiley & Sons: New York,
2
008; pp 105-135. (b) Yoshida, J.-I. Chem.;Eur. J. 2008, 14 (25), 7450.
(8) Johnson, B. K.; Prud’homme, R. J. AIChE J. 2003, 49, 2264.
DOI: 10.1021/jo102275n
r 2011 American Chemical Society
Published on Web 01/06/2011
J. Org. Chem. 2011, 76, 993–996 993