Measurement of Concentration of Reaction Intermediate in Microreactors Using a Raman Microscope Spectrometer

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

Yoshiki OKADA*, Kazuki NITTA, Teijirou TANAKA, Satoshi KUDOH

Graduate School of Science and Engineering, Kansai University,

3-3-35 Yamate-cho, Suita-shi, Osaka 564-8680, Japan

Keywords: Microreactor, Reaction Intermediate, Raman Microscopic Spectrometry, Cyclohexene, Bromination

Reaction

In microreactors, which comprise extremely narrow channels, a fluid is in laminar flow. The flow is constant spatially and temporally, and therefore, reactant concentrations are defined spatially, resulting in constant reactions. Consequently, the concentrations of reaction intermediates generated in microreactors are also defined spatially and are always constant. Regulation of the concentrations of the reaction intermediates enables efficient control of the reactions. In this study, we developed a basic technique for reaction control in microreactors by

Raman microscopic spectrometry and showed that the concentrations of the reaction intermediates are spatially defined as unique values that are dependent on the reactant concentration.

* Corresponding author: [email protected], Tel: 06-6368-0868, Fax: 06-6388-8869

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

Introduction

A microreactor is a tubular reactor having 1–1000-μm-sized channels (microchannels), and is fabricated using semiconductor device fabrication technology, which is also known as micro-electro-mechanical systems (MEMS) technology. Reaction fluids flow through these channels. Development of micro chemical processes, in which products are obtained from reactions carried out under strict conditions within the microspace, is being aggressively pursued in the field of chemistry and in biochemical analysis (pharmaceuticals, foods, and fine chemicals).

To date, in the field of chemical engineering, the production rate has been increased by scaling up reactors.

However, the volume of a microreactor is too small for the mass production of products on a plant scale. Hence, mass production in this case is achieved not by using a single microreactor but by using the numbering-up method, in which many microreactors or microchannels are integrated (Kusaka and Sotowa, 2008). Construction of chemical plants using microreactors, namely micro chemical plants, and production on a commercial scale have been attempted.

The key aims of flash chemistry, in which extremely fast reactions are carried out in microreactors, are generation of highly reactive chemical species and control of extremely fast reactions for the selective synthesis of the desired compounds. In particular, in reactions involving short-lived reaction intermediates, precise control of the reaction time leads to an improvement in the yield of the desired products (Kusaka and Sotowa, 2008; Yoshida et al., 2008). There are some reports in which the yield was improved by controlling residence time and the mixing time using microreactors (Moffatt-Swern-type oxidation (Kawaguchi et al., 2005), Kolbe-Schmitt synthesis (Hessel et al., 2007)). When the yield of the products depends on the concentration of the intermediates, as in the case of Swern oxidation, it is critical to control the concentration of the intermediates for achieving high product yields (Kano et al., 2008).

In microreactors, which have extremely narrow channels, a fluid is in laminar flow. Therefore, the concentration of a reactant at an arbitrary point in the microreactors is always constant; further, the concentration of a reaction intermediate is also constant, and depends on the reactant concentration. Thus, when a point is spectrally analyzed, a particular value that is dependent on the concentration should be obtained as the spectral intensity of the reaction intermediate (Mozharov et al., 2011). Utilizing the steady-flow feature supported in microreactors, we have developed a technology for measuring reaction intermediates, which are unstable reactive species. We measure the concentration of these intermediates using a Raman microscope spectrometer, which can observe a local point, and demonstrate that the concentration of the reaction intermediates is a unique value that is

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012 dependent on the reactant concentration.

1. Reaction system

In this study, we carried out the bromination of cyclohexene (a fast reaction), which proceeds as shown in

Equation (1).

Br 2/benzene + Br- Br （１） (1) cyclohexene inter med iate Br product trans -1,2- dibromocyclohexane

2. Experiment

Observations were conducted using a Raman microscope spectrometer (NRS-3100, JASCO Corporation). As shown in Fig. 1, a heater with temperature control system (OKS-C107, OKT7070-ULC, OKANO ELECTRIC

WIRE Co.) and a Y-shaped Pyrex microreactor (Institute of Microchemical Technology Co.) were mounted on the

X-Y-Z stage of the Raman microscope spectrometer. Reactant solutions were introduced via two inlets into the

Y-shaped microreactor by using microsyringes and allowed to react at the junction. At that instant, the spatial concentration distribution of the solution in the microreactor was observed using the Raman microscope spectrometer by precise movement of the X-Y-Z stage in increments of 0.1 μm along the three dimensions. A trace amount of the reaction intermediate in the reaction region was detected and used to investigate the dependence of the Raman peak intensity of the reaction intermediate on the reactant concentration. The Y-shaped microreactor used in this study was constructed by stacking three Pyrex glass plates; the detailed structure is shown in Fig. 1.

Before the commencement of the experiment, the spatial resolution of the Raman microscope spectrometer used in this study was measured using a silicon plate. First, a laser beam was focused at the center of the silicon plate to obtain the intensity of the Raman peak of silicon. Next, the Raman intensity was measured by moving the silicon plate mounted on the X-Y stage at 0.1-μm intervals from the initial position (where the laser beam did not impinge on the silicon plate), in the direction in which the laser beam impinges, to the final position (where the

Raman intensity of the silicon peak same as that of the first one was detected). On the basis of the distance from the edge of the silicon plate to the point where the Raman intensity was the same as that detected at the center, the laser beam diameter was estimated to be approximately 18 μm. Therefore, the spatial resolution in the horizontal direction was found to be approximately 18 μm. The spatial resolution in the depth direction was found to be approximately 20 μm. This was on the basis of the fact that when the change in the Raman spectrum of the

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012 microreactor filled with the solution was measured by moving the stage in the Z-axis direction, the intensity of the peaks corresponding to the solution decreased and that of peaks corresponding to the glass sandwiching the solution increased when the stage was moved over a distance of approximately 20 μm along the Z-axis.

Firstly, the Raman spectra of the reactants, products, and solvent were measured to determine the wavenumbers of the Raman peaks specific to these substances. Next, to determine the concentrations of the reactants on the basis of the Raman peak intensity, the reactants were introduced into the microreactor using syringe pumps.

Raman spectra were recorded at five arbitrary points in order to measure the Raman peak intensity of the reactants.

Since absolute values of the Raman peak intensity of the reactants varied with respect to the measurement points in the microreactor, a solvent, benzene, was used as the internal standard, and values relative to the Raman intensity of benzene were adopted instead of the absolute values. At some points in the microreactor, the relative

Raman peak intensities of the reactants to benzene were measured, and measurement errors were evaluated on the basis of spatial dispersion.

Benzene was used as the solvent, and the reactants were bromine and cyclohexene solutions. The concentration of bromine was 1.0 mol/l and that of cyclohexene was 0.503 mol/l; the concentration of the solvent, benzene, in both the solutions was 10.6 mol/l. The prepared solutions were introduced into the microreactor using two syringes through two inlets at a flow rate of 10 μl/min. The microreactor was heated to 55 °C.

On the basis of the idea that long time measurement of the Raman spectra would allow us to detect Raman peaks of the reaction intermediate present in trace amounts, the Raman spectra were accumulated for a long time such as ten minutes at around the interface 50 μm downstream from the junction. Moreover, the Raman spectra were also measured at the points 0.5, 2.5, 5, and 25 mm downstream of the junction.

3. Results and discussion

Raman peaks specific to bromine (306 cm-1), cyclohexene (823 cm-1), trans-1,2-dibromocyclohexane (652 cm-1), and benzene (609 cm-1) were observed in the Raman spectra shown in Fig. 2. Measurement of the Raman peak intensity of substances at these wavenumbers allows us to identify each substance and measure its concentration from the complex Raman spectra of the reaction system comprising many substances.

Figures 3 and 4 show the relationship between the molar concentrations of the bromine and cyclohexene solutions and the Raman intensities of the reactants (bromine and cyclohexene) relative to the intensity of benzene; the Raman intensities are obtained from measurements of the Raman peak intensity at different reactant

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012 concentrations. These graphs show that the reactant concentrations are directly proportional to the relative values of the Raman intensity. Therefore, the molar concentrations of the reactants can be calculated from the relative

Raman peak intensities of the reactants.

Bromine and cyclohexene solutions were introduced into the microchannels, and the Raman spectra were measured at around the interface 50 μm downstream of the junction. Figure 5 shows the Raman spectra of the reaction system, reactants (bromine and cyclohexene), product (dibromocyclohexane), solvent (benzene), and

Pyrex glass. In the Raman spectrum of the reaction system ①, the Raman intensity peaks near 265 cm-1 were detected only at around the interface. These Raman peaks were not attributed to the reactants, product, solvent, or

- Pyrex glass. It is well known that the polybromide anions Brn (n = 3, 5, 7) are stably present for bromination of alkene in aprotic solvents (Ruasse, 1993; Chiappe et al., 2006). It was found experimentally and theoretically that

- -1 Br5 has a strong Raman band around 250 cm , which is assigned to a terminal symmetric stretching mode (Chen et al., 2010; Bauer et al., 1997). Therefore, we believe that the 265 cm-1 peaks we observed originate in a bridged

- - bromonium cation formed as the reaction intermediate – Br5 complex. The bridged bromonium cation – Br3

- complex, which is thought to be present at larger concentration than the bridged bromonium cation – Br5 complex,

-1 - should have a Raman band around 160 cm , assigned to a symmetric stretching mode of Br3 . We could not, unfortunately, observe the Raman band, because the band was overlapped with a large peak of the reactant.

By Raman microscopic spectrometry used in our microreactor, we could observe the reaction intermediate in the bromination of cyclohexene. From this result, we guess that reaction intermediates in the bromination of other alkenes will be able to be observed in microreactors by the present method.

Figure 6 shows the relative Raman peak intensities of the reaction intermediate, measured at different points downstream of the junction. This plot indicates that the concentration of the reaction intermediate is maximum at the point 50 μm downstream of the junction, and that the concentration decreases as the distance from the junction increases. This is probably because of the active reaction between the high concentrations of the reactants

(bromine and cyclohexene) at the interface near the junction. It is guessed that the reaction proceeds at the points that are further downstream; at these points, the reactant concentration decreases, because of which the reaction intermediate also decreases.

Br k1 k2 Br+ - ＋ Br2 ＋ Br

cyclohexene intermediate Br product trans-1,2- (CHX) dibromocyclohexane (CHX*)

Let the rate constants of the above reaction be k1 and k2; thus, the rate equation for the reaction intermediate, 5

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

rCHX*, can be given by the following equation:

- rCHX* = k1[CHX][Br2]-k2[CHX*][Br ] (2)

Because the reaction intermediate produced is consumed immediately, the net reaction rate should be extremely small. Therefore, it is assumed that Equation (3) can be used for steady-state approximation.

rCHX* = 0 (3)

Then, the concentration of the reaction intermediate is obtained using the following equation:

k1 2][CHX][Br (4) [CHX*] - k 2 ][Br

Since the stoichiometric coefficients of [CHX*] and [Br-] are 1,

[Br-] = [CHX*] (5)

Substitution of Equation (5) into Equation (4) yields the following equation for calculating the concentration of the reaction intermediate:

k1 (6) [CHX*]  2 ][CHX][Br k2

This equation indicates that the concentration of the reaction intermediate, [CHX*], is proportional to the square root of the product of the concentrations of the reactants, . 2 ][CHX][Br

The Raman peak intensities of the reactants and the reaction intermediate were measured at different points downstream of the junction in the Y-shaped microreactor. Then, on the basis of values of the Raman peak intensities of the reactants and reaction intermediate measured with respect to the internal standard, the relationship between and the relative values of the Raman peak intensity of the reaction intermediate, 2 ][CHX][Br

[CHX*], was obtained. The obtained result is shown in Fig. 7. Measurements were repeated 5–7 times at each observation point. The experimental data yield a line that passes through the origin, and satisfy Equation (6).

Consequently, the fact that the concentration of the reaction intermediate depends on the reactant concentrations was confirmed. Moreover, because the reaction rate at each spatial point is determined on the basis of the concentration of the reaction intermediate, the reaction rate is defined as a unique value that is dependent on the constant values of reactant concentrations at each spatial point.

4. Conclusions

In this study, the bromination of cyclohexene (a fast reaction) was carried out in a microreactor, and the Raman spectra of the reactants and products were measured. First, it was found that there were proportional relations

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012 between the reactant concentrations and the Raman peak intensity. Further, the Raman peaks of the reaction intermediate were successfully detected. It was confirmed that the Raman peak intensity of the reaction intermediate depends on the reactant concentration, as shown theoretically. Thus, we developed a basic technology for reaction control in microreactors and showed that reaction rate is spatially defined as a unique value.

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

Literature Cited

Bauer, G., Drobits, J., Fabjan, C., Mikosch, H., Schuster, P.; “Raman Spectroscopic Study of the Bromine Storing

Complex Phase in a Zinc-flow Battery,” J. Electroanalytical Chem., 427, 123-128 (1997)

Chen, X., Rickard, M. A., Hull Jr., J. W., Zheng, C., Leugers, A., Simoncic, P.; “Raman Spectroscopic

Investigation of Tetraethylammonium Polybromides,” Inorg. Chem., 49, 8684-8689 (2010)

Chiappe, C., Pomelli, C. S., Lenoir, D., Wattenbach, C.; “The First Intermediates in the Bromination of Bicyclo

[3.3.1] Nonylidenebicyclo [3.3.1] Nonane, Combination of Experiments and Theoretical Results,” J. Mol.

Model, 12, 631-639 (2006)

Hessel, V., Hofmann, C., Lob, P., Lowe, H., Parals, M.; “Microreactor Processing for the Aqueous Kolbe-Schmitt

Synthesis of Hydroquinone and Phloroglucinol,” Chem. Eng. Technol., 30, 355-362 (2007)

Kano, J., Tonomura, O., Kano, M., Hasebe, S.; “Chukantai no Noudoseigyo wo Mokuteki to shita Maikuroriakuta

no Sekkei (in Japanese) [Design of Microreactors to Control Concentration of Intermediates],” L20,

Proceedings of the 40th Autumn Meeting of the Society of Chemical Engineers, Japan, (2008)

Kawaguchi, T., Miyata, H., Ataka, K., Mae, K., Yoshida, J.-i.; “Room-temperature Swern Oxidations by Using a

Microscale Flow System,” Angew. Chem., Int. Ed., 44, 2413-2416 (2005)

Kusakabe, K., Sotowa, K.; “Maikuroriakuta Nyumon (in Japanese) [An introduction to microreactors],” pp. 4, 6-7,

47-48, 61-63, 126-128, 152-154, Yoneda shuppan, Japan (2008)

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Kinetic Studies in Microreactors Using Flow Manipulation and Noninvasive Raman Spectrometry,” J. Am.

Chem. Soc., 133, 3601-3608 (2011)

Ruasse, M. -F.; “Electrophilic Bromination of Carbon-carbon Bouble Bonds: Structure, Solvent and Mechanism,”

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Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

Figure captions

Fig. 1 Schematic representation of experimental apparatus

Fig. 2 Raman spectra of pure substances

Fig. 3 Relationship between bromine concentration and Raman peak intensity

Fig. 4 Relationship between cyclohexene concentration and its Raman peak intensity

Fig. 5 Raman spectra of the reaction system, reactants, product, solvent, and Pyrex glass; measurements were

performed at a point 50 μm downstream of the junction (enlarged)

Fig. 6 Change in the Raman peak intensity of the reaction intermediate with the distance from the junction

Fig. 7 The dependence of the reaction intermediate on the reactant concentrations

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

Syringe pump ； Raman laser (Harvard Apparatus PHD 2000)

Microreactor

X-Y-Z stage

Cross section of reactor

Depth 70μm Raman microscopic spectrometer Beaker Width 230μm (JASCO Corporation ： NRS-3100)

Details of the Y-shaped microreactor ・ Angle of the intersection of two channels: 45 ° ・ Dimensions of the cross section downstream of the junction: 230 μm (width) × 70 μm (depth) (aspect ratio: 3.3) ・ Channel length downstream of the junction: 40 mm

Fig. 1 Y. Okada et al.

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

bromine/benzene cyclohexene trans-1,2-dibromocyclohexane benzene

[-] intensity Raman

800 600 400 wavenumber [cm-1]

Fig. 2 Y. Okada et al.

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

bromine

to standard substance [-] Raman intensity ratio bromine of 0 0 0.2 0.4 0.6 0.8 1 concentration [mol/l]

Fig. 3 Y. Okada et al.

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

0.4 cyclohexene

0.3

0.2

0.1 to standard substance [-] 0 0 0.1 0.2 0.3 0.4 0.5 Raman intensity cyclohexene of ratio concentration [mol/l]

Fig. 4 Y. Okada et al.

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

①reaction system ②bromine/benzene ③cyclohexene/benzene ④trans-1,2-dibromocyclohexane ⑤benzene ⑥pyrex glass

Raman intensity [-] intensity Raman

280 270 260 250 -1 wavenumber [cm ]

Fig. 5 Y. Okada et al.

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

0.08

0.06

0.04

0.02

to standard substance [-] 0 0 1000010 2000020 distance from mixing point [mm]

Raman intensity reaction ratio of intermediate

Fig. 6 Y. Okada et al.

Journal of Chemical Engineering of Japan, Advance Publication doi: 10.1252/jcej.12we033; published online on March 30, 2012

0.08

0.06

0.04

[CHX*]

0.02

0 0 1 2 3

2 ]Br][CHX[

Fig. 7 Y. Okada et al.