Passflow syntheses using functionalized monolithic polymer/glass composites in flow-through microreactors

Article abstract of DOI:10.1002/1521-3773(20011105)40:21<3995::AID-ANIE3995>3.0.CO;2-V

A chemist's wish finally becomes reality: microreactors for every synthetic laboratory! By precipitation polymerization various polymers are introduced into the irregular pore system of a porous glass rod. By embedding these rods into a housing, followed by functionalization and immobilization of reagents onto the polymer phase, versatile microreactors are obtained. With this apparatus, chemical transformations in solution can be performed, for example, a steroid derivatization (see picture).

Full text of DOI:10.1002/1521-3773(20011105)40:21<3995::AID-ANIE3995>3.0.CO;2-V

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arises as a result of an acceleration in the oxidative part of the
process. The decreasing activity at larger alcohol concentra-
tions may originate from the concomitant decrease in the
water concentration. Consequently, the reductive reaction
step may become too slow to efficiently compete with
recombination of the charge carriers. The ammonia produced
is further photooxidized to nitrate through traces of oxygen
present in the system.
[15] K. Hoshino, M. Inui, T. Kitamura, H. Kokado, Angew. Chem. 2000,
1
12, 2558; Angew. Chem. Int. Ed. 2000, 39, 2509.
[
16] a) D. L. Boucher, J. A. Davies, J. G. Edwards, A. Mennad, J. Photo-
chem. Photobiol. A 1995, 88, 53; b) J. G. Edwards, J. A. Davies, D. L.
Boucher, A. Mennad, Angew. Chem. 1992, 104, 489; Angew. Chem.
Int. Ed. Engl. 1992, 31, 480.
[
[
17] S. K. Gupta, V. Rajakumar, P. Grieveson, Metall. Trans. B 1991, 22,
7
11.
18] V. Schünnemann, A. X. Trautwein, O. Rusina, A. Eremenko, H.
Kisch, unpublished results.
Aqueous solutions of sodium formate and humic acids of
proper concentration also function as reducing agents. Since
the latter compounds are ubiquitous in nature and Fe Ti O
7
[19] Unless otherwise noted all the following data correspond to the
Fe Ti film.
2
2 7
O
[
20] a) O. A. Ileperuma, W. C. B. Kiriden, W. D. D. P. Dissanayake, J.
Photochem. Photobiol. A 1991, 59, 191; b) G. N. Schrauzer, T. D. Guth,
J. Salehi, N. Strampach, N.-H. Liu, M. R. Palmer in Homogeneous and
Heterogeneous Photocatalysis (Eds.: E. Pelizzetti, N. Serpone),
Reidel, Dordrecht, 1986, p. 509; c) W. R. McLean, M. Ritchie, J.
Appl. Chem. 1965, 15, 452; d) H. Mozzanega, J.-M. Herrmann, P.
Pichat, J. Phys. Chem. 1979, 83, 2251; e) P. Pichat, J.-M. Herrmann, H.
Courbon, J. Disdier, M.-N. Mozzanega, Can. J. Chem. Eng. 1982, 60,
2
2
phases could be formed through oxidative weathering of
ilmenite in sunlight, this novel reaction may be an example of
a light-driven nonenzymatic nitrogen fixation under natural
[
23]
conditions.
2
7; f) C. H. Pollema, E. B. Milosavljevich, J. L. Hendrix, L. Solujic,
Experimental Section
J. H. Nelson, Monatsh. Chem. 1992, 123, 333.
[
[
21] O. Rusina, A. Eremenko, W. Macyk, H. Kisch, unpublished results.
22] V. Augugliaro, L. Palmisano, M. Schiavello, Photocatalysis and
Environment. Trends and Applications, Kluwer, Amsterdam, 1988,
p. 425.
23] G. N. Schrauzer, N. Strampach, H.-N. Liu, M. R. Palmer, J. Salehi,
Proc. Natl. Acad. Sci. USA 1983, 80, 3873.
After fast immersing a glass slide (26 Â 76 mm) into an ethanolic solution of
Ti(OiPr)
4
and FeCl
3
(Fe:Ti ˆ 1:1 or 2:1) it was pulled out at a speed of
�
1
6
cmmin and left in air for 15 min. The film was subsequently tempered
for 20 min at 6008C. Irradiations were performed on an optical train
equipped with a high-pressure Hg lamp (HBO200) mounted at a distance
of 35 cm from the solidex glass cuvette (l ꢀ 320 nm, 80 Â 40 Â 10 mm)
which contained the glass slide. Unless otherwise noted, a film with a Fe:Ti
[
[
24] J. Kruse, M. G. Mellon, Sewage Ind. Wastes 1952, 24, 1098.
ratio of 1:1 was employed and unpurified dinitrogen was permanently
‡
bubbled through the suspension. The concentration of NH
4
ions was
determined colorimetrically according to the method of Kruse and
Mellon;[ the resulting absorbancies at 450 nm were in the range of 0.01
to 2.10. Blank experiments in the absence of the glass slide did not induce
the formation of significant amounts of ammonia. The reproducibility of
the film preparation was excellent as evident by the ammonia concen-
trations agreeing within Æ10%. Nitrite and nitrate were measured by ion
chromatography (Dionex-120, Ion Pac AS 14 column, conductivity detec-
24]
PASSflow Syntheses Using Functionalized
Monolithic Polymer/Glass Composites in
Flow-Through Microreactors**
Andreas Kirschning,* Carsten Altwicker,
Gerald Dräger, Jan Harders, Nora Hoffmann,
Ulrich Hoffmann, Hagen Schönfeld,
�
1
tor, NaHCO
3
:Na
2
CO
3
ˆ 0.001:0.0035 molL as eluting agent).
Received: November 27, 2000
Revised: June 7, 2001 [Z16176]
Wladimir Solodenko, and Ulrich Kunz*
After an ªincubation timeº of more than 25 years interest in
polymer-supported reagents for the solid-supported synthesis
in solution has increased dramatically of late.[ In this
technique reagents or catalysts are immobilized on a solid
[
[
[
1] G. N. Schrauzer, T. D. Guth, J. Am. Chem. Soc. 1977, 99, 7189.
2] P. P. Radford, C. G. Francis, J. Chem. Soc. Chem. Commun. 1983, 1520.
3] a) E. Endoh, A. J. Bard, Nouv. J. Chim. 1987, 11, 217; b) E. Endoh,
J. K. Leland, A. J. Bard, J. Phys. Chem. 1986, 90, 6223.
1]
[
[
4] N. N. Lichtin, K. M. Vijayakumar, J. Indian Chem. Soc. 1986, 63, 29.
5] a) V. Augugliaro, A. Lauricella, L. Rizzuti, M. Schiavello, A. Sclafani,
Int. J. Hydrogen Energy 1982, 7, 845; b) V. Augugliaro, F. DꢁAlba, L.
Rizzuti, M. Schiavello, A. Sclafani, Int. J. Hydrogen Energy 1982, 7,
[*] Prof. Dr. A. Kirschning, Dr. G. Dräger, N. Hoffmann,
Dr. W. Solodenko
Institut für Organische Chemie der Universität Hannover
Schneiderberg 1B
851.
[
6] M. M. Khader, N. N. Lichtin, G. H. Vurens, M. Salmeron, G. A.
Somorjai, Langmuir 1987, 3, 303.
3
0167 Hannover (Germany)
[
[
7] H. Miyama, N. Fujii, Y. Nagae, Chem. Phys. Lett. 1980, 74, 523.
8] a) N. N. Rao, S. Dub, Manjubala, P. Natarajan, Appl. Catal. B 1994, 5,
Fax : (‡49)511-762-3011
E-mail: andreas.kirschning@oci.uni-hannover.de
33; b) M. I. Litter, J. A. Navio, J. Photochem. Photobiol. A 1996, 98,
Dr.-Ing. U. Kunz, Dr.-Ing. C. Altwicker, Prof. Dr.-Ing. U. Hoffmann,
H. Schönfeld
Institut für Chemische Verfahrenstechnik der Technischen Universität
Clausthal
171.
[
9] a) P. L. Yue, F. Khan, L. Rizzuti, Chem. Eng. Sci. 1983, 38, 1893;
b) M. M. Taqui Khan, D. Chatterjee, M. Bala, J. Photochem. Photo-
biol. A 1992, 67, 349.
Leibnizstrasse 17, 38678 Clausthal-Zellerfeld (Germany)
Fax : (‡49)5323-72-2182
[
[
[
[
[
10] J. Soria, J. C. Conesa, V. Augugliaro, L. Palmisano, M. Schiavello, A.
Sclafani, J. Phys. Chem. 1991, 95, 274.
E-mail: kunz@icvt.tu-clausthal.de
11] A. Sclafani, L. Palmisano, M. Schiavello, Res. Chem. Intermed. 1992,
Dr. J. Harders
1
8, 211.
12] L. Palmisano, V. Augugliaro, A. Sclafani, M. Schiavello, J. Phys. Chem.
988, 92, 6710.
Institut für Organische Chemie der Technischen Universität Clausthal
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld (Germany)
1
13] V. Augugliaro, J. Soria, Angew. Chem. 1993, 32, 579; Angew. Chem.
Int. Ed. Engl. 1993, 105, 550.
14] L. Palmisano, M. Schiavello, A. Sclafani, Angew. Chem. 1993, 105,
[**] Part of these studies were supported by the Fonds der Chemischen
Industrie and the European Community (EC project number HPRI-
CT-1999-00085) for which we are grateful. PASSflow ˆ Polymer
Assisted Solution-Phase Synthesis technique in flow-through mode.
579; Angew. Chem. Int. Ed. Engl. 1993, 32, 550.
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support, in many cases, crosslinked polystyrenes have been
used for this purpose. The intrinsic advantages of this hybrid
solid-phase/solution-phase technique lie in the simple purifi-
cation and the possibility to use these reagents in excess to
drive reactions in solution to completion. The opportunity to
employ this technique in conjunction with continuous-flow
processes is particularly appealing as this application would
create an ideal almost workup-free technique for automated
solution-phase synthesis.[2]
interiors with a stable shape. The polymer particles inside the
pore volume can swell and shrink only in the pore volume,
whereas the outer dimensions of the rod stay stable. Technical
problems like bypassing or high pressure drop as observed in
pure polymer packings can be avoided.
These chemically functionalized rods were first embedded
inside a solvent-resistant tube. This was followed by encap-
sulation with a pressure-resistant fiber reinforced epoxy resin
housing with two standard high-pressure liquid chromatog-
raphy (HPLC) fittings (Figure 2). A particular difficulty
However, there are two key criteria to be considered when
constructing a stoichiometrically working flow-through reac-
tor. These are high loading and good accessibility of the
soluble reactant to the active immobilized species. Both
criteria can be controlled by the right choice of the solid
support. For polymeric supports the degree of cross-linking is
[
3, 4]
essential.
For kinetic reasons a low degree of cross-linking
is desired. This feature leads to gels, which as a result of
swelling in organic solvents such as THF or dichloromethane
which makes the immobilized species more accessible. How-
ever, filled in tubes these polymers either block the flow (and
cause a pressure drop) when swollen or, when shrunk, create a
gap between the inner wall of the flow-through reactor and
the polymer allowing the solution to bypass the polymer.
Herein we present the PASSflow (Polymer Assisted
Solution-Phase Synthesis flow-through mode) technique,
which allows solid-phase supported synthesis in solution to
be performed in a flow-through mode. This concept is based
on a monolithic flow-through microreactor, which is loaded
with polymer-bound reagents or catalysts and allows organic
transformations in solution to be performed with a low to
moderate pressure drop. Essentially, the monolithic block
contains a novel, chemically functionalized, highly porous
polymer/glass composite. Polyvinylchlorobenzene (cross-
linked with 2 ± 20% of divinylbenzene) is prepared by
precipitation polymerization in the pore volume of highly
porous glass rods to yield a polymeric matrix inside the rod
Figure 2. Schematic set up of the PASSflow reactor; PTFE ˆ polytetra-
fluoroethylene.
associated with monolithic flow-through reactor systems is the
suppression of the fluid bypass and forcing the fluid to flow
through the microchannels of the rod. Dynamic NMR
spectroscopy microscopic visualization with water as a fluid
clearly showed that no solvent bypass is detected for this flow-
through reactor for a pressure up to 20 bar.[ In the example
reported here, the benzylic chlorine function was aminated
with triethylamine in toluene to yield the corresponding
polymer-anchored quaternary ammonium ion. The resulting
strongly basic ion-exchange resin was loaded with various
anions. The synthetic properties of these chemically function-
alized flow-through reactors were tested with fundamental
transformations such as substitution, oxidation, and reduction
(Table 1).
7]
[
5, 6]
(Figure 1).
The polymeric structures obtained are small
The monolithic reactors (about 10 cm in length, about
5 mm diameter, about 10 to 20 mass% (ca. 1 mmol) polymer
loading) enable the preparation of up to 1 mmol of product in
shorter times than reactions promoted with conventional
polymer-bound reagents. This is demonstrated for the reduc-
tion of actophenone to 1-phenylethanol using polymer-bound
borohydride (Figure 3). As expected, the reaction rate is
much faster when the solvent is forced to flow through the
microchannels of the monolithic reactor than when a bare
polymer/glass composite rod is placed in a beaker of reactant
solution or with a finely powdered borohydride-impregnated
composite material.[ This result clearly demonstrates that the
combination of a highly porous chemically inert glass rod and
a functionalized polymer anchored inside the pores guaran-
tees a short diffusion path for the soluble organic reactants
and products and in addition enables a good convectional
flow.[
beads (1 ± 5 mm diameter), and are all cross-linked with
polymeric bridges. This property results in a monolithic
polymeric phase, with a high surface area, which is wedged
inside the microchannel pore system of the support. Even
under forced convectional flow the polymer phase can not be
washed out of the reactor. Furthermore, having a polymeric
phase inside the fixed matrix of glass rods leads to reactor
8]
9]
To test the utility of our microreactors for the derivatization
of natural products or drugs, we employed three differently
functionalized PASSflow reactors, modified with the oxidizing
anion 2,[ the fluoride anion 4, and the reducing anion 6. In a
three-step sequence the partially O-silylated steroid 1 was
transformed into the aminoderivative 7 (Scheme 1). Only
10]
Figure 1. Scanning electron microscope image of the polystyrene/glass
composite. The scale bars correspond to 10 mm (left) and 500 nm (right).
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Table 1. Reactions performed with the PASSflow reactor.
Starting material
Chemical functionalization in the reactor
Conditions
Product
+
–
O
OH
NMe3 BH4
MeOH, 608C, 6 h
Ph
Me
Ph
Me
OH
O
+
–
NMe3 Br(OAc)2
cat TEMPO
2 2
CH Cl , RT, 6 h
+
–
NMe3 Nu
Nu ˆ N
3
C
6
H
6
, 708C, 12 h
Ph
Nu
Ph
Br
Nu ˆ CN
C
C
6
6
H
H
6
6
, 708C, 12 h
, 708C, 12 h
Nu ˆ SCN
O
CHO
Nu ˆ
Toluol, 758C, 24 h
[
a] The products were isolated after removal of the solvent. In each case the yield was >95%; according the NMR spectra the purity was >95% for all cases.
bound bromate(i) anion 2 gave ketone 3, which was desilyl-
ated to afford alcohol 5 after being pumped through a fluoride
4
loaded PASSflow reactor. The sequence was terminated by a
reductive amination step in which the imine was generated
in situ from ketone 5 with benzyl amine and the resulting
solution was pumped through a microreactor loaded with
borohydride to furnish amine 7 and small amounts of the
corresponding diol.
In summary, we have developed a microreactor which can
be incorporated into any conventional HPLC system. The key
component is a novel monolithic composite material which is
composed of a macroporous glass and a functionalized
polymer. Changing the functionalization of the polymer
allows various reactions to be efficiently performed in the
flow-through mode. With this new reactor concept a cost-
effective laboratory tool is available allowing easy flow-
through applications in organic chemistry. This offers a high
potential for automated polymer-assisted solution-phase syn-
thesis.[
Figure 3. Borohydride-promoted reduction of acetophenone: reaction
course using different composites (
microreactor, * bare chunks of
monolithic glass rod, ~ powdered composite).
&
12, 13]
Experimental Section
Preparation of polymer/glass monoliths and application in organic syn-
thesis: Polymerization: vinylbenzyl chloride (45 g) and divinylbenzene
(
3.9 g; 65% ethylbenzene) was dissolved in C14 ± C17 n-paraffin (300 mL).
After dissolution of azoisobutyronitrile (300 mg) porous glass rods with a
diameter of 5.3 mm and a length of 110 mm were immersed in this solution.
Air was removed from inside the pore volume by applying a vacuum for a
short time. After heating at 708C overnight, the rods were cleaned of any
adhering polymer and rinsed with trichloromethane.
Amination: The rods loaded with the polymer were covered with dry
toluene and a continuous flow of trimethylamine was passed through this
solution. After 4 days the rods were removed from the solution and dried in
vacuo. Then, the rods, now functionalized with quarternary ammonium
cations, were fitted with a casing and could be used as microreactors in
organic synthesis.
Scheme 1. Polymer-assisted three-step derivatization of a steroid in PASS-
flow reactors; TEMPO ˆ 2,2,6,6-tetramethylpiperidine N-oxide OAc ˆ
acetate.
Exchange with bromate(i) anions 2 and successive oxidation of 1: The
microreactor (chloride ion loaded) was treated with: deionized water
(
10 mL), sodium hydroxide solution (1m, 10 mL), deionized water (10 mL),
hydrobromic acid (2m, 10 mL), deionized water (10 mL), methanol
10 ml), and dry dichloromethane (25 mL). After this procedure, a solution
of 1.5 mmol diacetoxyiodinebenzene in dry dichloromethane (10 mL) was
pumped through the reactor under argon in a recycle mode for one night.
anions were immobilized which ensures the simple regener-
ation of the reactor column after each reaction.[11] The
TEMPO-catalyzed oxidation of alcohol 1 with the polymer-
(
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After washing with dry dichloromethane (10 mL), the compound 1
An Analytical Approach for a Comprehensive
Study of Organic Aerosols**
(
0.125 mmol) and a catalytic amount of TEMPO (0.1 mol%) in dry
dichloromethane (10 mL) were pumped in a recycle mode under argon for
h through the reactor. The reactor system was rinsed with dichloro-
6
Wolfgang Schrader,* Jutta Geiger,
Markus Godejohann, Bettina Warscheid, and
Thorsten Hoffmann
methane (10 mL) and the combined organic solvents were removed in
vacuo and the residue was used for the further reactions without additional
purification.
Received: May 17, 2001 [Z17127]
Since the first scientific explanation of the so-called ªblue
hazeº phenomenon above forests by Went,[ the formation of
natural organic aerosol particles in the atmosphere and their
impact on the climate has drawn considerable attention.
Airborne particles absorb, reflect, and scatter incoming solar
radiation, play an important role in cloud droplet formation,
and may even be involved in multiphase atmospheric
chemistry.[
1]
[
1] Recent reviews: a) A. Kirschning, H. Monenschein, R. Wittenberg,
Angew. Chem. 2001, 113, 670 ± 701; Angew. Chem. Int. Ed. 2001, 40,
50 ± 679; b) A. Kirschning, H. Monenschein, R. Wittenberg, Chem.
6
Eur. J. 2000, 6, 4445 ± 4450; c) S. V. Ley, I. R. Baxendale, R. N. Bream,
P. S. Jackson, A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I.
Storer, S. J. Taylor, J. Chem. Soc. Perkin Trans. 1 2000, 3815 ± 4195;
d) D. H. Drewry, D. M. Coe, S. Poon, Med. Res. Rev. 1999, 19, 97 ± 148.
2] ªPolymer Reagents and Catalystsº: R. T. Taylor, ACS Symp. Ser. 1986,
2]
In recent reports it was established that especially the
reaction of mono- and sesquiterpenes with tropospheric
ozone contributes to the formation of organic aerosols,[
however, our knowledge about reaction mechanisms leading
to low-volatile products is still limited. Making things difficult
is the fact that during the ozonolysis free OH radicals are
formed that have to be considered.[
[
[
3
08, 132 ± 154.
3]
3] Reviews: a) D. Hudson, J. Comb. Chem. 1999, 1, 333 ± 360; D. Hudson,
J. Comb. Chem. 1999, 1, 403 ± 457; b) A. R. Vaino, K. D. Janda, J.
Comb. Chem. 2000, 2, 579 ± 596; c) P. Hodge, Chem. Soc. Rev. 1997, 26,
4
17 ± 424.
[
[
4] S. Rana, P. White, M. Bradley, J. Comb. Chem. 2001, 3, 9 ± 15.
5] a) K. Sundmacher, H. Künne, U. Kunz, Chem. Ing. Tech. 1998, 70,
4]
However, the initial steps of the terpene ozonolysis in the
gas phase corresponds to known mechanisms,[ exemplified in
Scheme 1 for a-pinene 1, the most abundant single mono-
terpene released by plants. The first step is the formation of
the molozonide 2 that forms reactive Criegee intermediates
3a and 3b. Subsequent reactions lead to the formation of
several low vapor-pressure products, such as pinonic acid (4),
pinic acid (5), or hydroxy pinonic (6) acid which have been
identified using mass spectrometric methods.[ Although
possible mechanisms for the generation of these carboxylic
products have been suggested,[ the overall understanding of
the reaction mechanisms leading to condensable species is still
inadequate.
2
67 ± 271; b) C. Altwicker, Dissertation, TU Clausthal, 2001.
5]
[
[
[
6] By employing monomers such as 4-vinylpyridine other polymers can
be incorporated into the porous glass rod by precipitation polymer-
ization.
7] These studies were conducted as part of European-funded project at
the center for NMR spectroscopy of the University of Wageningen
(
The Netherlands).
8] Under these conditions, gel-type (Amberlite IRA 400) as well as
macroporous (Amberlite IRA 900) anion-exchange resins loaded
with borohydride anions, both of which are commercially available,
behave similarly to the bare monolithic rod and the powdered
material, respectively.
6]
7]
[
9] Depending on the extent of polymer swelling caused by the solvent
�
1
used the pressure drop was 10 bar (3 mLmin
)
and 28 bar
�
1
(10 mLmin ), respectively, across a length of the reactor.
[
[
10] G. Sourkouni-Argirusi, A. Kirschning, Org. Lett. 2000, 2, 3781 ± 3784.
11] For automation common HPLC equipment can be used (e.g. pumps,
detectors, valves, dosing facilities).
[
12] S. J. Haswell, R. J. Middleton, B. OꢁSullivan, V. Skelton, P. Watts, P.
Styring, Chem. Commun. 2001, 391 ± 398.
13] The flow-through reactors presented are available from CHELO-
NA GmbH (Potsdam).
[*] Dr. W. Schrader
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim/Ruhr (Germany)
Fax : (‡49)208-306-2982
[
E-mail: wschrader@mpi-muelheim.mpg.de
Dr. J. Geiger
Institut für Spektrochemie und angewandte Spektroskopie (ISAS),
Institutsteil Berlin
Albert-Einstein-Strasse 9, 12489 Berlin-Adlershof (Germany)
Dr. M. Godejohann
Bruker Analytik GmbH
7
6287 Rheinstetten, Silberstreifen (Germany)
Dipl.-Chem. B. Warscheid, Dr. T. Hoffmann
Institut für Spektrochemie und angewandte Spektroskopie (ISAS),
Institutsteil Dortmund
Bunsen-Kirchhoff-Strasse 11, 44139 Dortmund (Germany)
[
**] The financial support by the Bundesministerium für Bildung und
Forschung and the Senatsverwaltung für Wissenschaft, Forschung und
Kultur des Landes Berlin (ISAS Berlin), and the Ministerium für
Schule, Wissenschaft und Forschung NRW (ISAS Dortmund) is
gratefully acknowledged. The authors want to thank U. Marggraff and
W. Nigge (Dortmund) for assistence during MS measurements and Dr.
R. Köppe (Univ. Karlsruhe) and Dr. H. Sievers (GSG Karlsruhe) for
assistance in FT-ICR-MS measurements.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
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