Optical fiber-based on-line UV/Vis spectroscopic monitoring of chemical reaction kinetics under high pressure in a capillary microreactor

Article abstract of DOI:10.1039/b500429b

With a miniaturized (3 μL volume) fiber-optics based system for on-line measurement by UV/Vis spectroscopy, the reaction rate constants (at different pressures) and the activation volumes (ΔV^≠) were determinined for a nucleophilic aromatic substitution and an aza Diels-Alder reaction in a capillary microreactor. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b500429b

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Optical fiber-based on-line UV/Vis spectroscopic monitoring of
chemical reaction kinetics under high pressure in a capillary
microreactor{
a
Fernando Benito-Lopez, Willem Verboom,* Masaya Kakuta, J. (Han) G. E. Gardeniers,*
a
b
b
a
b
b
Richard J. M. Egberink, Edwin R. Oosterbroek, Albert van den Berg and David N. Reinhoudt
a
Received (in Cambridge, UK) 12th January 2005, Accepted 8th April 2005
First published as an Advance Article on the web 22nd April 2005
DOI: 10.1039/b500429b
With a miniaturized (3 mL volume) fiber-optics based system
for on-line measurement by UV/Vis spectroscopy, the reaction
rate constants (at different pressures) and the activation
A schematic representation of the microreactor set-up is given in
Fig. 1. It consists of a fused silica capillary (volume of 3 mL)
running through a stainless steel cross, a 6-port valve for sample
inlet and outlet, and a HPLC pump as pressure generator. Via an
optical fiber, connecting the silica capillary and an UV/vis
spectrophotometer, the course of the reactions was followed.
High pressure sources delivering pressures up to several hundreds
of bars are generally available for HPLC, a rather common
analytical method, which can be used without the exceptional
safety regulations that normally apply in high-pressure chemistry
labs. Although high-pressure fluidic connections and valves are still
?
volumes (DV ) were determinined for a nucleophilic aromatic
substitution and an aza Diels–Alder reaction in a capillary
microreactor.
Application of (high) pressure is a very important methodology to
1
enhance the rate of a variety of organic reactions. In general,
reactions accompanied by a decrease in molar activation volume
?
(DV ) are accelerated by pressure. The molar activation volume of
4
a reaction (the difference in molar volume between the
intermediate state and the reactants) provides valuable information
on the mechanism of a (bio)chemical reaction and the molecular
intermediates involved in it.
a problem in lab-on-a-chip systems, for our applications we used
the commercially available connectors which were tested up to
700 bar, and can be used in a capillary-based microreactor system
without adjustment.
5
In general, high-pressure chemistry is regarded as a technique
that requires specialized equipment with strict safety precautions.
It is trivial that miniaturization of the reaction system will relax
safety regulations, so that high pressure experimentation will
become more readily available. Therefore, we decided to build a
miniaturized microreactor platform for the study of the pressure
dependence of (the rate of) organic reactions. The ultimate goal is
to build a microsystem for parallel synthetic organic chemistry,
Some years ago Ibata et al. reported that nucleophilic aromatic
substitution reactions of electron-withdrawing group containing
aromatic halides with various amines could be accelerated by
pressure. This type of reaction proceeds via a Meisenheimer
dipolar intermediate. The effect of pressure on this reaction is
explained by the fact that both bond formation and charge
separation occur in the transition state.
We selected this reaction to study it in more detail in our
microreactor set-up. Therefore p-halonitrobenzenes (1) (X 5 F, Cl,
Br) were reacted with a ten-fold excess of pyrrolidine (2a),
piperidine (2b), and morpholine (2c) in THF at 1, 200, 400, and
600 bar to give the p-N,N-dialkylamino-nitrobenzenes (3a–c)
2
based on the ‘‘Lab-on-a-chip’’ concept, which has integrated
components for on-line chemical analysis and reaction control, like
thin film heaters or a miniaturized electrochemical pressure source,
3
which has been demonstrated to achieve pressures over 1300 bar.
As a first step towards such a system, we describe in this
communication a miniaturized experimentation platform based on
conventional HPLC tools coupled to a capillary microreactor. As
a proof-of-concept a capillary-based system has been used to study
the pressure dependence of organic reactions at pressures of up to
600 bar. Although this pressure range does not give the full
advantage of high pressure chemistry, the range is wide enough to
study the rate enhancement and to collect essential information to
determine the molar activation volumes of reactions. To monitor
the course of the reactions, a fiber-optic system for on-line UV
spectroscopy is used.
{
Electronic supplementary information (ESI) available: plots of the
reaction of 1b with 2a under different pressures, Table with rate constants
of the reaction of halonitrobenzenes 1 with amines 2, and Table with rate
constants and activation volumes of the reaction of 1a with amines 2a,b.
See http://www.rsc.org/suppdata/cc/b5/b500429b/
Fig. 1 Schematic representation of the high pressure UV capillary
reactor system showing: high pressure generator (a), six-port valve for
injection (b), capillary microreactor (c), optical fiber (d), UV/Vis light
source (e), and UV/Vis detector (f).
*w.verboom@utwente.nl (Willem Verboom)
j.g.e.gardeniers@utwente.nl (J. (Han) G. E. Gardeniers)
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Chem. Commun., 2005, 2857–2859 | 2857

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Table 1 Rate constants for the nucleophilic aromatic substitution
reaction of halonitrobenzenes 1 with amines 2 at 600 bar
a
a
21
21 21
s
Halonitrobenzene
Amine
kobs/s
k/M
2
2
2
2
2
2
2
2
2
2
4
4
2
4
5
5
5
7
22
1
1
1
1
1
1
1
1
1
a
a
b
c
a
b
c
a
b
c
2a
2a
2a
2b
2b
2b
2c
2c
2c
3.86 6 10
6.95 6 10
8.25 6 10
1.10 6 10
3.62 6 10
3.22 6 10
9.87 6 10
6.76 6 10
2.17 6 10
3.09 6 10
5.56 6 10
6.60 6 10
8.80 6 10
2.89 6 10
2.57 6 10
7.89 6 10
5.41 6 10
1.74 6 10
24
24
23
24
25
25
25
27
Upon mixing 0.125 M halonitrobenzene 1 and 1.25 M amine 2.
observed in corresponding reactions using methoxide ion as a
7
nucleophile.
For the reaction with 1-fluoro-4-nitrobenzene (1a) Fig. 2 clearly
shows the expected order in reactivity between the amines 2:
5
,8
pyrrolidine . piperidine . morpholine, having rate enhance-
ments of 2.7, 1.7 and 1.5, respectively at 600 bar. A batch reaction
at lab scale, at 1 bar, resulted in k-values comparable to those
obtained with the microreactor, thereby excluding microreactor-
wall effects.
Scheme 1 Aromatic nucleophilic substitution (a) and aza-Diels–Alder
reaction (b).
(Scheme 1a). The product formation was monitored by the
increase of the absorption peak at 391 nm in the UV/Vis spectra.
Rate constants k of the different reactions at the different
pressures were calculated from the increase of the absorption at
?
(
hln k/hp)
T
5 2DV /RT
(2)
3
91 nm using a pseudo first order kinetic equation (eqn. 1). The
The activation volumes were calculated from a plot of the
second-order reaction rate constants versus pressure using eqn. 2;
they are summarized in Table 2. The most negative activation
volumes are found for the fastest reactions, e.g. the reaction of
resulting rate constant kobs has to be divided by the amine
concentration to obtain the second-order rate constant k.
A 5 A [1 2 exp(2kobst)]
‘
(1)
t
1-fluoro-4-nitrobenzene (1a) with pyrrolidine (2a). All these values
are in the same range as those reported in the literature for the
aromatic nucleophilic substitution reactions of bromoquinolines
Where A
t
is the absorbance at time t and A
‘
is that after infinite
time. As an illustration, Fig. 2 shows the second order rate
constants k of the reaction of 1-fluoro-4-nitrobenzene (1a) vs.
pressure for the three different amines (2). The rate constants (kobs
and k) at 600 bar are summarized in Table 1.
9
and bromonaphthalenes with piperidine.
It is known that nucleophilic aromatic substitution reactions of
halonitrobenzenes with secondary amines can be base catalyzed,
1
0
the amine also being the catalyst. An example is the reaction of
The k values show the following reactivity order of the leaving
6
groups: F . Cl . Br. However, in the case of pyrrolidine (2a),
1
1
12
2,4-dinitrohalobenzenes with morpholine, piperidine, and ani-
9
line. To investigate this catalytic effect, the reactions of 1-fluoro-4-
1
-bromo-4-nitrobenzene (1c) reacts somewhat faster than the
21 21
2
4
nitrobenzene (1a) with pyrrolidine (2a) and piperidine (2b) were
performed at different amine concentrations. The same approx-
imations by pseudo-first order kinetics as described above were
used. Although the approximation is not valid in all cases,
meaningful results were still obtained. Plots of the second-order
rate constants vs. the pyrrolidine or piperidine concentrations pass
through the origin and have a positive slope (Fig. 3). This indicates
corresponding chloro derivative (1b) (6.60 6 10
M
s
, vs.
2
4
21 21
5.56 6 10
M
s
at 600 bar). A similar behavior has been
13
that the reactions are amine catalyzed.
?
3
21
Table 2 Activation volumes DV (cm mol ) for the reactions of
halonitrobenzenes 1a–c with amines 2a–c
a
Amine
a
Halonitrobenzene
Pyrrolidine
2
Piperidine
2b
Morpholine
2c
a
b
b
1a
1b
1c
a
258
241.7
232.7
232.4
223.3
217.3
222.5
218.2
214.5
Upon mixing 0.125 M halonitrobenzene 1 and 1.25 M amine 2.
The errors for the reactions of 1a with 2a and 1b with 2b are 0.4
and 0.1 cm mol , respectively, after five different experiments.
Fig. 2 Nucleophilic aromatic substitution reaction of 1-fluoro-4-nitro-
benzene (1a) (0.125 M) with amines 2a–c (1.25 M) in THF at four different
pressures.
b
3
21
2
858 | Chem. Commun., 2005, 2857–2859
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M. K. would like to thank Dr Miyoshi (Tokushima Univ.,
Japan) for kind suggestions. This research is supported by the
Technology Foundation STW, applied science division of NWO
and the technology program of the Ministry of Economic Affairs.
a
Fernando Benito-Lopez, Willem Verboom,* Masaya Kakuta,
a
b
b
J. (Han) G. E. Gardeniers,* Richard J. M. Egberink,
a
b
Edwin R. Oosterbroek, Albert van den Berg and David N. Reinhoudt
b
a
a
Laboratory of Supramolecular Chemistry and Technology (SMCT),
MESA Institute for Nanotechnology, University of Twente, P.O. Box
+
2
17, 7500 AE, Enschede, The Netherlands.
E-mail: w.verboom@utwente.nl; Fax: +31 (0)53 489 4645;
Tel: +31 (0)53 489 2977
BIOS-Lab-on-a-chip group, MESA Institute for Nanotechnology,
b
+
University of Twente, P.O. Box 217, 7500 AE, Enschede, The
Netherlands. E-mail: j.g.e.gardeniers@utwente.nl;
Fax: +31 (0)53 489 2287; Tel: +31 (0)53 489 4356
Notes and references
1
R. van Eldik and F. G. Kl a¨ rner, in High Pressure Chemistry, eds. R. van
Eldik and F. G. Kl a¨ rner, Wiley-VCH, Weinheim, 2002.
Fig. 3 Piperidine (2b) concentration dependence at different pressures
for the reaction with 1-fluoro-4-nitrobenzene (1a) in THF.
2 Lab-on-a-chip: Miniaturized systems for (bio)chemical analysis and
synthesis, eds. R. E. Oosterbroek and A. van den Berg, Elsevier,
Amsterdam, 2003.
3
S. Bohm, H. van der Linden, A. van den Berg, W. Olthuis and
P. Bergveld, Proc. mTAS 2000 Symp. May 14–18, Enschede, The
Netherlands, Kluwer Academic Publishers, Dordrecht, 2000, p. 611.
1
4
Usually Diels–Alder reactions have rather high negative
?
3
21 15
activation volumes (DV # 225 to 245 cm mol ), which
make them susceptible to pressure.
4 S. M. Stishov and A. E. Pretova, Instrum. Exp. Tech., 2003, 46, 719.
5
T. Ibata, Y. Isogami and J. Toyoda, Bull. Chem. Soc. Jpn., 1991, 64, 42;
T. Ibata, M. H. Shang and T. Demura, Bull. Chem. Soc. Jpn., 1995, 68,
16
Recently, Yuan et al. reported that at room temperature the
aza Diels–Alder reaction of Danishefsky’s diene 4 with imines in
methanol gave 2-substituted dihydro-4-pyridone derivatives in
good yield. Although the reaction proceeds already at room
temperature, the reaction of Danishefsky’s diene 4 with imine 5 to
give 1,2-diphenyl-dihydro-4-pyridone (6) (Scheme 1b) in methanol
was studied in our set-up at different pressures. The product
formation was monitored by the increase of the absorption at
2
941.
6 G. Bartoli and P. E. Todesco, Acc. Chem. Res., 1977, 10, 125.
7
8
G. P. Brynner, M. Leveris, P. G. Lutz and J. Miller, J. Chem. Soc.,
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T. Ibata, X. Zuo and T. Demura, Tetrahedron Lett., 1993, 34, 5613.
1
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0 T. A. Emokpae and C. Isanbor, Int. J. Chem. Kinet., 2004, 36, 188;
1
J. F. Bunnett and R. H. Garst, J. Am. Chem. Soc., 1965, 87, 3875.
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1
12 J. F. Bunnett and C. F. Bernasconi, J. Org. Chem., 1970, 35, 70.
?
3
21
335 nm in the UV/Vis spectrum. A DV of 233 cm mol was
1
3 C. Isanbor, T. A. Emakpae and M. R. Crampton, J. Chem. Soc., Perkin
Trans. 2, 2002, 2019.
calculated using eqn. 2. This value is in agreement with those of
related Diels–Alder reactions such as e.g. the reaction of furan with
?
1
4 K. Matsumoto, A. Sera and T. Uchida, Synthesis, 1985, 1;
K. Matsumoto and A. Sera, Synthesis, 1985, 999; M. Ciobanu
and K. Matsumoto, Liebigs Ann. Rec., 1997, 623; F. G. Kl a¨ rner
and B. M. Diedrich, in: The Chemistry of Dienes and Polyenes,
3 21
furan-2,5-dione (DV 5 230.5 cm mol ) and 9-(hydroxymethyl)-
?
3
21 17
anthracene with N-ethylmaleimide (DV 5 231.4 cm mol ).
In conclusion, to the best of our knowledge, this simple set-up is
the first example in which a reaction under high pressure can be
monitored on-line. In addition, an important advantage of the set-
up is that high-pressure reactions can be studied without the
extensive safety precautions that are required for conventional
high-pressure instrumentation.
(
Z. Rappoport, ed.), Vol. 1, p. 547, Wiley, New York, 1997.
5 J. R. McCabe and C. A. Eckert, Acc. Chem. Res., 1974, 7, 251;
C. Brun, G. Jenner and A. Deluzarche, Bull. Soc. Chim. Fr., 1972,
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6 Y. Yuan, X. Li and K. Ding, Org. Lett., 2002, 4, 3309.
7 A. Drljaca, C. D. Hubbard, R. van Eldik, T. Asano, M. V. Basilevsky
and W. J. Le Noble, Chem. Rev., 1998, 98, 2167.
1
2
1
1
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Chem. Commun., 2005, 2857–2859 | 2859