Surface effects in the esterification of 9-pyrenebutyric acid within a glass micro reactor

Article abstract of DOI:10.1039/b305226p

Surface phenomena are an important contribution to the chip effect , leading to higher yields and shorter reaction times, as demonstrated for the acid-catalysed esterification of 9-pyrenebutyric acid within a glass fabricated micro reactor.

Full text of DOI:10.1039/b305226p

Surface effects in the esterification of 9-pyrenebutyric acid within a glass
micro reactor
a
b
a
b
Monica Brivio, R. Edwin Oosterbroek, Willem Verboom,* Martijn H. Goedbloed, Albert van den
b
a
Berg and David N. Reinhoudt*
Laboratory of Supramolecular Chemistry and Technology, MESA Research Institute, University of
Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands. E-mail: smct@utwente.nl; Fax: +31 53
a
+
4
894645; Tel: +31 53 4892980
b
+
BIOS, MESA Research Institute, University of Twente, P.O. Box 217, 7500 AE Enschede, The
Netherlands
Received (in Cambridge, UK) 9th May 2003, Accepted 16th June 2003
First published as an Advance Article on the web 27th June 2003
Surface phenomena are an important contribution to the
chip effect”, leading to higher yields and shorter reaction
times, as demonstrated for the acid-catalysed esterification
of 9-pyrenebutyric acid within a glass fabricated micro
reactor.
flow conditions. During the experiments the chip was placed in
“
a holder (Fig. 1b) designed for fitting fused silica fibers into the
inlet/outlet chip reservoirs by means of commercially available
Upchurch Nanoport™ assemblies. Using these fittings allows
reagent injection in a continuous flow fashion, eliminating the
risk of adhesive contamination and offering the great advantage
of adding only insignificantly low dead volume to the flow path.
The reagent flows were controlled by two 100 µl syringes,
mounted on a microdialysis pump. The reaction products were
directly transferred from the outlet silica fiber to a Matrix-
Assisted Laser Desorption ionization Time of Flight (MALDI-
TOF) mass spectrometer sample plate in a continuous flow
fashion by collecting individual droplets, after which the
samples on the plate were analyzed batch-wise. After the
individual droplets were placed on the plate, the solvent quickly
evaporates so that no further reaction could take place. In this
way the reaction-to-analysis delay time is eliminated, which is
inherent to off-line chip analysis. High Pressure Liquid
Chromatography (HPLC) was used for the quantitative determi-
nation of the conversions.
In the past two decades the rapid development of micro-
fabrication technologies and the corresponding design strate-
gies have given an enormous impetus to progress in the field of
microfluidics. Not only for analytical applications,1 but,
recently, micromachining technologies have also been applied
to synthetic organic chemistry leading to the development of
micro reactors. In general, miniaturization is a valuable tool to
decrease time and costs of performed processes. Furthermore,
significant enhancements in efficiency of mixing and separa-
–4
5
,6
7
tion and increased selectivity and safety can be achieved,
when performing chemical reactions in microfluidic devices. A
number of liquid and gas phase reactions have been demon-
strated to show improved reactivity in terms of product yield
and selectivity when performed on the microscale, as compared
8
to conventional lab-scale equipment. Most microscale synthe-
ses such as Wittig reaction,
The target reaction was performed both in glass microchips
9,10
11
enamine formation, aldol
and in conventional lab-scale glassware. All experiments were
12
13,14
24
reaction, preparation of enolates from diketones
and
carried out under the same conditions using solutions of 10
M
peptide synthesis,1
5,16
have been carried out under electro-
9-pyrenebutyric acid 1 in ethanol and of 10 M sulfuric acid in
ethanol both at room temperature and at 50 °C.
24
kinetic fluidic (EOF) control. The improved reactivity found for
these reactions has mainly been attributed to the high degree of
spatial and temporal reaction control achievable in the electro-
kinetically driven micro reaction system.8 Other features that
enhance the reactions in micro reactors involve the fast
diffusive mixing under laminar flow conditions and the high
No ester formation could be detected in aliquots taken from
a lab scale experiment at 4, 10, 20, 30, and 40 min at both room
temperature and 50 °C. However, in the on-chip experiments
carried out at room temperature, about 15–20% of ester 2 was
already formed after 40 min. When the on-chip experiments
were performed at 50 °C higher yields of ester 2 were obtained.
The dependence of the conversion on the residence time is
clearly demonstrated in the MALDI-TOF mass spectra (Fig. 2),
while the yields are summarized in Table 1. These results
clearly show the large positive effect of a glass microchip on the
target reaction.
To study the possible influence of the silanol groups at the
inner channel surface, the on-chip experiments summarized in
Table 1 were repeated at room temperature and at 50 °C,
without injecting the sulfuric acid. No ester 2 could be detected
in any of the collected samples. However, when activating the
glass surface hydroxy goups by pretreating the channel with a
solution of sulfuric acid and hydrogen peroxide (3 : 1), 9% of
,17
efficiency of heat transfer.18
†
Only a few examples of organic reactions performed in a
pressure-driven glass micro reactor have been reported in the
literature.1
9–21
In this communication we present the consider-
able increase in reaction efficiency observed in a systematic
study of the acid-catalysed esterification of 9-pyrenebutyric
acid 1 with ethanol (Scheme 1),22 performed in a microchannel
with a high surface to volume ratio.
The borosilicate micro reactor (Fig. 1a) used in this study was
+
prepared in the cleanroom laboratories of the MESA Research
Institute. High precision powderblast micromachining was used
for the fabrication of inlet and outlet connections, while the
reaction microchannel was made with HF chemical etching.
The on-chip reactions were carried out in a 197 mm long, 200
µm wide and 100 µm deep microchannel under pressure-driven
Fig. 1 Pictures of (a) the glass micro reactor and (b) the self-developed chip
Scheme 1
holder.
1
924
CHEM. COMMUN., 2003, 1924–1925
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ester 2 was formed in the glass microchannel after 40 min at 50
C. These results demonstrate the active role of the micro-
channel glass surface on the formation of ester 2.
times in the on-chip experiments (Table 1). This clearly
indicates a higher efficiency of the micro- over the macroscale
reaction.
°
To exclude that the rate enhancement is partially due to the
dynamics of mixing at the microscale, the esterification was
repeated in a fused silica fiber with an inner diameter (100 µm)
comparable with that of the micro reactor channel. The silica
fiber was filled with a premixed 1 : 1 solution of carboxylic acid
Upon miniaturization there is an increasing surface to volume
ratio. The importance of chip-surface phenomena has already
been described for electroosmotic flow-based microreactors,
1
7
the first example of which was the Suzuki coupling performed
by Greenway et al.,23 and particularly in nanochannels. To the
best of our knowledge, we have presented for the first time a
systematic study of the influence of the channel surface in
pressure-driven glass microchips illustrated for the acid-
catalysed esterification of 9-pyrenebutyric acid 1. Our results
clearly demonstrate the important contribution of surface
phenomena to the “chip effect”, giving rise to much shorter
reaction times and higher yields than on conventional lab
scale.
24
1
and sulfuric acid in ethanol, and heated at 50 °C for 2, 4, 8, 10,
and 20 min, respectively. The MALDI-TOF mass spectra of the
samples showed that the conversions at comparable residence
times were similar to those obtained in the corresponding on-
chip experiments. Subsequently, the experiments were repeated
in a glass fiber, the inner surface of which was coated by
reaction of the SiOH groups with the lipophilic octadecyltri-
chlorosilane. However, no product formation could be detected,
again substantiating the effect of the microchannel surface on
the esterification reaction. Probably, the large number of acidic
hydroxy groups within the glass micro reactor and the uncoated
silica fiber activate the ethanol, present in large excess,
facilitating the esterification.
The authors like to thank Jeroen Bode for the synthesis of
ester 2 and Avantium B.V. for financial support.
Finally, the same reaction was done at lab-scale in the
presence of silica gel, imitating the same glass-surface to
chemicals-volume ratio ( ~ 1 : 34). At reaction times of 4, 10,
Notes and references
†
This esterification reaction was selected since it has a relatively short
reaction time and in addition, the progress can be easily monitored with
MALDI-TOF ms on account of the presence of the pyrene group.
2
0, and 40 min conversions of 8%, 9%, 10%, and 15%,
respectively, were obtained at 50 °C. The conversions are
substantially lower than those obtained at the same residence
1
2
3
4
5
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Table 1 Yieldsa of ester 2 obtained in the on-chip and lab scale (in the
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Yield (%)
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21
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On-chip
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33
51
71
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Yields were determined by HPLC, using a LUNA 3 µm C18 (2) column
dimensions: 100 3 4.60 mm). A 60 : 40 mixture of acetonitrile and an
aqueous solution of 20 mM NaH PO at pH = 4.3 was used as eluent. From
2
3 G. M. Greenway, S. J. Haswell, D. O. Morgan, V. Skelton and P.
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(
2
4
2
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t = 0 up to t = 25 min the mixture composition was changed in a gradient
resulting in 100% acetonitrile at t = 25 min. The initial composition was
finally regenerated to the initial value (60:40) at t = 30 min.
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