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Fast and Efficient Acquisition of Kinetic Data in Microreactors Using In-Line Raman Analysis Sebastian Schwolow,†,⊥ Frank Braun,‡,⊥ Matthias Rad̈ le,‡,§ Norbert Kockmann,∥ and Thorsten Röder*,†

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on August 24, 2015 | http://pubs.acs.org Publication Date (Web): August 14, 2015 | doi: 10.1021/acs.oprd.5b00184

†

Mannheim University of Applied Sciences, Institute of Chemical Process Engineering, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany ‡ Mannheim University of Applied Sciences, Institute of Process Control and Innovative Energy Conversion, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany § Heidelberg University and Mannheim University of Applied Sciences, Institute of Medical Technology, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany ∥ TU Dortmund University, Biochemical and Chemical Engineering, Equipment Design, Emil-Figge-Straße 68, 44227 Dortmund, Germany S Supporting Information *

ABSTRACT: This study demonstrates that a microreactor setup with fast in-line reaction monitoring by Raman spectroscopy can be a highly efficient laboratory tool for kinetic studies and process development. Using a coaxial probe and commercial spectrometer to perform real-time measurements in the microchannel prevents the need for reaction quenching, sampling, and time-consuming off-line analysis methods such as GC or HPLC. A specially designed, temperature-controlled aluminum plate microreactor was developed and tested in the exothermic synthesis of 3-piperidino propionic acid ethyl ester by Michael addition. In-line measurements through a fused quartz screen in the reactor channel, which had an increasing cross-sectional area, allowed time-series kinetic data to be collected over nearly the full range of reaction conversions. An optimum flow rate range in which nearly ideal plug flow behavior can be assumed was identified. Furthermore, a time gradient was applied to the reactant flow rates, and the product concentration was simultaneously and repeatedly measured at various locations in the reactor channel. With this approach, the experiment duration and material consumption are significantly reduced relative to those of conventional steadystate experiments. Two hundred data points with residence times ranging from 0.3 to 49 s were collected in less than 1 h. Thus, this method can be used for the high-throughput screening of reaction parameters in a microreactor.

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INTRODUCTION Microreactor systems have proven to be an effective tool for process intensification and reaction development.1 The process conditions of microreactors can be precisely defined due to their well-defined flow patterns, high mixing performance, and efficient heat removal. When these reactors are employed in combination with laboratory automation systems, the reaction conditions can be screened to obtain kinetic information using a fully automated procedure, making the experiments materialand time-efficient. In these types of studies, sampling and offline product analysis by HPLC or GC are often the timelimiting steps. Furthermore, the reaction must be rapidly and effectively quenched to determine the product compositions at specific reaction times. The data acquisition time can be reduced remarkably by integrating modern spectroscopic detection techniques into the reactor system for in-line analysis. Additional advantages of in-line analysis include the possible detection of unstable intermediates, control of the reaction progress by real-time monitoring, and inclusion of selfoptimizing algorithms in the laboratory automation system.2 On-line reaction monitoring of continuous microreactor systems has been accomplished using various spectroscopic methods, such as fluorescence, ultraviolet−visible (UV/vis), near- and mid-infrared (IR), and Raman spectroscopies.3 Further details on the detection techniques and their © XXXX American Chemical Society

integration into microreactor setups can be found in the literature.4 In mid-IR spectroscopy, the fundamental vibrations of structural groups are excited, and narrow bands are obtained, providing highly specific information for the identification of various molecular species. However, it is difficult to use this technique to control reactions in a microreactor process because thin optical layer thicknesses are required due to the high molecular extinction coefficients in the mid-IR region. Fiber optical materials, such as sapphire, chalcogenide glass, or hollow glass waveguides, are expensive and difficult to assemble. Furthermore, strong interference from water reduces the sensitivity of mid-IR spectroscopy in aqueous systems. Although near-IR spectroscopy is easier to implement for online and in-line process monitoring, overtones and combinations of fundamental vibrations result in broad bands, making the spectra difficult to interpret. In principle, Raman spectroscopy, which is often considered to be complementary to IR spectroscopy, combines the main advantages of near- and midIR technologies. This technique provides high chemical specificity, and it can be easily integrated into continuous processes by using common near-IR transmitting materials. In addition, the weak Raman signal of water does not interfere Received: June 8, 2015

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DOI: 10.1021/acs.oprd.5b00184 Org. Process Res. Dev. XXXX, XXX, XXX−XXX


Organic Process Research & Development

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with the signals of other species in aqueous systems. However, the distinctive fluorescence background of some materials overlaps with the Raman scattering peaks of interest. Furthermore, comparatively high concentrations and high laser power are required to overcome the low sensitivity. Safety regulations for eyes and skin must be observed, and the optical power has to be limited in hazardous areas. Along with higher costs compared to other spectroscopic methods, this prevents many researchers from using Raman spectroscopy. This study investigated the potential of an automated microreactor system with in-line Raman spectroscopic reaction monitoring for use in kinetic studies. A microreactor with an optimized channel design for fast and exothermic reactions was developed. Because common flow cells can only cover a limited range of reaction conversions at the reactor outlet, in-line measurements throughout the entire channel length were realized. The broad conversion range needed for reliable conclusions on the reaction kinetics could be obtained by switching between several measurement locations. A method for collecting kinetic data under nonsteady-state conditions was recently published by Moore and Jensen.5 The combination of this principle with multiple measurement locations was investigated as a novel approach for fast and efficient acquisition of kinetic data. Steady-state and nonsteady-state methods were compared using the synthesis of 3-piperidino propionic acid ethyl ester by Michael addition (Scheme 1) as a

Figure 1. Channel design of the aluminum/glass reactor with the numbered measurement locations 1 to 9 and a transition from 1 mm channel width to 2 mm channel width at location 6 (a), milled reactor channel in the mixing area (b), and CFD simulation of the flow velocity distribution at one measurement location when the total flow rate was 10 mL/min (Re = 164 with water, 20 °C) (c).

micromixer due to the high energy input resulting from the high flow velocities in the small channels and to a sharp flow redirection in the arrowhead mixer.7,8 The residence time channel consisted of a 1 mm channel (total volume of 0.5 mL) and a 2 mm channel (total volume of 1.5 mL). The 1 mm channel width enabled good temperature control at the reactor entrance, where the reaction is fast and hot spots might occur. As the conversion increases, the third-order Michael addition reaction rate decreases significantly; therefore, a 2 mm channel was employed to achieve high conversions at longer residence times. Measurement locations with diameters of 2 mm were integrated into the smaller channel (Figure 1b) to facilitate focusing the laser beam. The design of the measurement locations was optimized by CFD simulations (Figure 1c). At a total flow rate of 10 mL/min, the Reynolds number (Re = ud/ ν) was 164 at the measurement location inlet. Due to the induced secondary flow,9 the concentration distribution in the region of the focused laser beam could be assumed to be uniform. Furthermore, the secondary flow caused by repeatedly redirecting the flow by 90° (creating a zigzag pattern) made the radial concentration profiles more uniform during laminar flow. Measurements show that narrow residence time distributions and reactor behavior close to that of an ideal plug flow reactor can be obtained with this channel design. Experimental data on the residence time distribution for a similar reactor channel (2 mm channel width) is available in a recent publication.6 Flow channels for cooling water or a heat carrier (5 mm × 6 mm) were milled on the opposite side of the reaction plate. Thus, the reactor temperature could be uniformly maintained at a specified value, and the reaction heat of the Michael addition could be efficiently removed. Compared to common glass reactors, the aluminum/glass combination allows for significantly improved temperature control for exothermic reactions due to the high thermal conductivity of aluminum, which is over 100 times higher than that of glass (AlZnMgCu1.5, λ = 140 W/(m·K)). The results of an infrared camera temperature measurement and measurements of the channel surface roughness by white light interferometry can be found in the Supporting Information. Experimental Setup. 3-Piperidino propionic acid ethyl ester was synthesized without any solvent. However, because water acts as a catalyst in this reaction,10 piperidine was premixed with 10.2 wt % of water. Neat ethyl acrylate was used. For all of the experiments, the reactant feeds were mixed at

Scheme 1. Synthesis of 3-piperidino propionic acid ethyl ester

model reaction. The reaction behavior and a kinetic model of this reaction were described in a previous publication.6 The kinetic model (see Supporting Information), which is based on off-line GC analyses, was used as a reference to evaluate the new results obtained by more time- and material-efficient analysis methods. Because the Michael addition reaction is significantly accelerated by the addition of water, the weak spectroscopic signal of water is a crucial advantage of Raman analysis over near- and mid-IR spectroscopies.

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MATERIALS AND METHODS Reactor Design. For this study, a plate microreactor was designed and manufactured by mechanical precision milling of aluminum. The entire reactor channel was covered with a fused quartz plate, which was evenly pressed onto the reactor plate to avoid significant bypass flow. For a suitable reactor design, a first rough estimation of the reaction time scale and the heat of reaction should be available. In case of the Michael addition with a reaction time below 1 min and an adiabatic temperature increase of approximately 190 K, the applied reactor was optimized for a fast and exothermic reaction. The main factors considered in the reactor channel design (Figure 1a) were the mixing performance, residence time distribution, integration of the optical measurements, and heat transfer. The reactor had channels of various sizes, and each channel had a quadratic cross-sectional area. The reactants were preheated in 1 mm channels and mixed in 0.5 mm channels, which were arranged in an arrow-shaped geometry (Figure 1b). A high mixing performance could be obtained by this type of B




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equal flow rates. Hence, the molar ratio was 1.01 equiv of piperidine per equivalent of ethyl acrylate. Both feed streams were supplied by continuous syringe pumps (Syrdos 2, HiTec Zang GmbH, Germany) with 10 mL glass syringes. By using a laboratory automation system (LabBox and LabVision Software, HiTec Zang GmbH), the flow rate settings for both the steady-state experiments and experiments with a continuously decreasing flow velocity could be controlled. Cooling water was flowed through the channels on the other side of the reactor plate to maintain the reactor temperature at 25 °C. In-line Raman reaction monitoring was performed using a highly sensitive Raman system (MultiSpec Raman, tec5 AG, Germany) equipped with a coaxial probe (InPhotonics, Inc., USA). This Raman system is employed in process environments with a thermoelectrically cooled CCD array. Raman scattering was excited by a temperature-stabilized semiconductor laser source at 785 nm with a 500 mW output power (approximately 260 mW after losses from optical components) and then coupled into the optical fiber. The Stokes Raman spectra (300−3100 cm−1) were collected with an optical wavelength resolution of 5 cm−1. Figure 2 shows a

The second data acquisition method was based on a new approach developed by Moore and Jensen5 for rapidly generating kinetic data using in-line analysis. These researchers applied residence time gradients by manipulating the flow rate and thus generated conversion/residence time profiles at different temperatures. Further details on this approach can be found in their publication. In this study, all of the measurements performed with a residence time gradient were started under steady-state conditions with a total flow rate Q0 of 20 mL/min, resulting in a short initial residence time τ0 = Vr/Q0. From this starting point (t = 0), a constant gradient α was applied to the instantaneous residence time τins, which is calculated at each experiment time t using the equation τins = τ0 + αt (1) The time profile of the flow rate Q(t) is obtained from the following equation: Q (t ) =

Vr Vr = τins τ0 + αt

(2)

For each measurement location, the effective reactor volume Vr was defined as the channel volume between the mixer and the measurement location. The gradient coefficient α is given by α=

Vr ⎛ 1 1 ⎞ ⎟⎟ ⎜⎜ − tend ⎝ Q end Q0⎠

(3)

where Qend is the lowest flow rate at the end of the measurement (t = tend). Figure 3 shows the residence time and flow rate as a function of time at measurement location 8 when the gradient α was 0.057.

Figure 2. Schematic of the experimental setup for the Raman spectroscopic measurements in the microreactor channel.

schematic of the entire setup for performing measurements in the microreactor channel. The probe was connected to a Zpositioner, which allowed for tracking in the vertical direction. For lateral positioning, the reactor was firmly attached to an XY cross table. Prior to each measurement series, the focal point of the probe (approximately 150 μm spot diameter) was adjusted to the center of the measurement location by aiming it at the maximum signal intensity. Data Acquisition Methods. Two different data acquisition methods were employed to obtain kinetic information from the spectroscopic measurements performed in the reactor channel. Raman spectra were recorded under (1) steady-state conditions and (2) nonsteady-state conditions with a flow rate gradient. All of the steady-state measurements were performed after running the reaction at a constant flow rate for at least ten times the hydrodynamic residence time. Because the Raman signal intensity is sensitive to small deviations in the probe position, the spectra of both reactant streams were recorded at all of the measurement locations for each vertical and lateral probe position. Thus, normalized results could be obtained by calculating the chemical conversion. Steady-state measurements were performed in the reaction mixture using an integration time of 6.5 s and were repeated for each series of flow rates at different measurement locations.

Figure 3. Time profiles of the total flow rate Q, instantaneous residence time τins, and fluid element residence time τ in the nonsteady-state experiments at measurement location 8.

The reaction conversion in a fluid element passing the Raman probe depends on the residence time τ, which is the amount of time that the fluid element spends in the effective reactor volume from an initial time ti to the time of measurement tf : τ = tf − t i

(4)

For a fluid element traveling through the reactor volume with this residence time, the effective reactor volume is Vr =

∫t

tf i

Q (t ) d t =

∫t

tf i

Vr dt τ0 + αt

(5)

Integrating and rearranging eq 5 yields ti as a function of tf : C




τ0(1 − e−α) α Finally, substituting eq 6 into eq 4 yields

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t i = t f e −α −

(6)

τ ⎞ ⎛ τ = (1 − e−α)⎜tf + 0 ⎟ ⎝ α⎠

(7)

Hence, the residence time τ of fluid elements at the measurement location increases with the gradient (1 − e−α). In the experiments, when the residence time started to increase, the Raman spectra measurements were initiated and collected with integration times of 6.5 s at intervals of 13 s. Measurements were repeated with identical flow rate gradients (Q0 = 20 mL/min; Qend = 6 mL/min; tend = 150 s) at measurement locations 1 to 9 (Figure 1a). With the effective reactor volume Vr, the gradient coefficient α for each measurement location results from eq 3. The applied flow rate gradient was chosen to ensure that the measurement time scale was small compared to the time scale of the residence time gradient. For example, at the first measurement location where the reaction was the fastest, the residence time changed by only 0.03 s during the integration time. Raman Spectra. Figure 5 shows the typical Raman spectra obtained from measurements collected when a flow rate gradient was applied. They consist of spectra arising from piperidine, ethyl acrylate, and 3-piperidino propionic acid ethyl ester. The spectra of the pure compounds are shown in Figure 4 for comparison. The reaction mixture also included water,

Figure 5. Raman spectra collected in the reactor channel during cyclic measurements as the residence time increased from 0.9 s (blue line) to 2.6 s (red line).

quantified by calculating the difference between the intensities at 1550 and 1637 cm−1.

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RESULTS AND DISCUSSION Steady-State Experiments. To obtain reliable experimental kinetic data, the residence time must be clearly defined, and the reaction must start almost instantaneously. Thus, the following conditions must be met in the microreactor: (1) the residence time distribution in the reactor must be close to that in a plug flow reactor and (2) the chemical conversion rate cannot be limited by poor mixing. Therefore, the radial concentration profiles must become uniform quickly. This process can be significantly enhanced by the formation of secondary vortices,12 which is mainly determined by the flow velocities in the micromixer and in the zigzag channel. Conversely, at low flow rates, the flow behavior increasingly deviates from the ideal behavior, making the experimental results unreliable. In Figure 6, the steady-state conversions measured at different total flow rates are compared to those obtained by a kinetic model of the reaction based on previous experiments analyzed by off-line methods.4 The reaction volumes of all data series collected at the different measurement locations range from 0.1 to 1.6 mL. The ranges of the residence times overlap due to the variation in the flow rate at each location. Thus, nonkinetic limitations on the conversion, which depend on the flow velocity, can be identified. At high flow rates, the various data series are in good agreement with each other and with the kinetic model. The conversions decrease slightly at a flow rate of 4 mL/min, as shown in Figure 6, whereas the conversions deviate significantly from the kinetic model at the lowest flow rate of 2 mL/min (Re ≈ 30). These deviations can be partially explained by the reduced mixing efficiency because our results are in good agreement with those from other experimental investigations7 that showed that the mixing performance of a similar arrowhead micromixer decreased considerably when the flow rate was reduced from 8 to 2 mL/min. Additionally, the lower conversions obtained at low flow rates can be attributed to less secondary flow in the 90° redirections of the zigzag

Figure 4. Raman spectra of piperidine (a), ethyl acrylate (b), and 3piperidino propionic acid ethyl ester (c).

which has no significant Raman bands in the measurement range. The spectra are dominated by overlapping signals from the fused quartz cover up to 600 cm−1. Piperidine can be identified by a sharp Raman band at 813 cm−1, whereas the band at 760 cm−1 is characteristic of the product. Ethyl acrylate exhibits a band at 1637 cm−1, which can be assigned to its characteristic vinyl stretching mode.11 Because this band is welldefined and does not overlap with the bands of other compounds, it was used to determine the reaction conversion. The inset in Figure 5 shows the decrease in this band with increasing residence time in the nonsteady-state experiments. To perform a simple baseline correction, this peak was D



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Figure 6. Comparison of the ethyl acrylate conversions determined by in-line Raman spectroscopy under steady-state conditions to those obtained by the kinetic model of Schwolow et al.6

Figure 7. Comparison of the ethyl acrylate conversions determined by in-line Raman spectroscopy under nonsteady-state conditions to those obtained by the kinetic model of Schwolow et al.6

Method Efficiency. Previously published kinetic investigations of the Michael addition reaction that utilized off-line analysis techniques were performed with an automated microreactor system, continuous quench system, autosampler, and gas chromatography.6 The completion of a time series with one set of parameters and ten data points, including the sample preparation and GC analyses, required approximately 3 h. Large amounts of solvent with a flow rate ratio of 10:1 were required to effectively quench the reaction. In this study, the experiments required to obtain the same amount of data were performed in only 20 min under steadystate conditions by employing a microreactor setup with in-line Raman spectroscopic reaction monitoring. By increasing the residence time at a constant gradient, the reaction time was further reduced to less than 3 min while simultaneously increasing the number of data points. Because the reaction could be monitored at different locations in the reactor channel, the residence time could be varied by a factor of 163 between 0.3 and 49 s. In contrast, when the reaction was monitored by a flow cell at the reactor outlet, the range of possible residence times was limited by the range of suitable flow rates for the microreactor system. Therefore, several microreactors with different inner volumes were required to study the secondorder reaction at both low and high conversions, which added to the time required to change the setup and clean the reactor. Based on these considerations, the amount of time required to conduct the experiments to determine the rate constant for one set of reaction conditions was estimated (Table 1). In-line analysis reduces the experimental time because the effective reaction volume can be rapidly changed by changing the probe position. Additionally, time-consuming sample preparation procedures and GC analyses are not required before the results can be evaluated. In the nonsteady-state experiments, the experimental time, which mainly depends on the residence

channel and in the measurement locations. As a result, the residence time distributions are broader, leading to deviations from ideal plug flow behavior in the reactor. The reproducibility of the results was investigated by repeated measurements including repeated adjustments of the Raman probe position. For measurements at flow rates above 4 mL/min, standard deviations in the reaction conversion were below 2%. Higher standard deviations were found for low flow rates (approximately 4% at 2 mL/min). Hence, the flow rates in this microreactor should be limited to the range of 6−20 mL/min for a reaction mixture with the same viscosity as that used in this study (Re = 100−330). Higher flow rates are possible in microreactors, but they are not beneficial because they require higher material consumption and lead to larger pressure drops in the reactor. Nonsteady-State Experiments. Equation 7, which is used to calculate the residence time of a fluid element from the gradient α, is only valid for nearly ideal plug flow behavior. Thus, the aforementioned requirements are even more important for the nonsteady-state experiments. Hence, the flow rates were limited to those at which the mixing conditions did not affect the reactor performance in the steady-state experiments (Figure 6). All of the data obtained from the experiments in which residence time gradients were applied at the eight different measurement locations in the reaction channel are shown in Figure 7. Again, the results do not systematically deviate from those obtained by the kinetic model based on off-line GC analysis. The standard deviation between the model and experimental nonsteady-state conversions is 3.1%, which is even lower than that between the model and experimental steadystate conversions (3.6% for the results acquired in the same flow rate range (6−20 mL/min)). E



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Table 1. Estimated time requirements to determine the conversion−time relation experimentally using at least 30 data points Off-line analysis (GC), steady state In-line analysis (Raman), steady state In-line analysis (Raman), nonsteady state

Experiment

Analysis

4h 3h 1h

6h Instantaneous Instantaneous

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Brief description of the used kinetic model; IR camera temperature measurement; measurement of the surface roughness (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Telephone: +49 621 292 6800.


Author Contributions ⊥

time gradient α, can be further reduced, making the nonsteadystate technique a highly efficient method for kinetic studies. For example, the 200 data points shown in Figure 7 were measured at eight different locations in the reactor channel in less than 1 h. The efficiency would be further improved by the use of a motorized cross table in the experimental setup. Hence, the probe position could be changed by an automated procedure to investigate the full residence time range, which could then be repeated for reaction parameter screening. Alternatively, the realization of multipoint measurements with a fiber multiplexer would enable simultaneous data acquisition at several measurement locations during the residence time gradient program.

Funding

This work was funded by the German Federal Ministry of Education and Research (BMBF, Funding Code 03FH012I2) and the German Federation of Industrial Research Associations (AiF Project GmbH, Funding Code 2035756LW3). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank Andreas Neumü ller (Hochschule Mannheim, Germany) for constructing and manufacturing the plate microreactor, Dr. Hanns Simon Eckhardt (tec5 AG, Germany), for providing the Raman probe and technical support, and Michael Ruland (Hochschule Mannheim, Germany) for measurements of the surface roughness.

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CONCLUSIONS In this study, an approach for combining microreactor technology with fiber-optic Raman spectroscopy was described and optimized for kinetic studies of rapid exothermic reactions. This reactor setup is advantageous compared to the use of flow cells for spectroscopic analysis because measurements can be performed at different locations throughout the channel. Thus, a large range of residence times could be explored while keeping the flow rate within a relatively small range. This advantage is crucial because the optimal flow rate range is limited by the dependence of the reactor behavior on the flow velocity. In these experiments, nonkinetic limitations due to poor mixing or dispersion effects are observed at flow rates below 6 mL/min. Instead of employing several reactors of different sizes, channels with different cross-sectional areas were combined. Hence, reaction data could be collected at both high and low conversions by varying the measurement location. Our results are in excellent agreement with those obtained by a kinetic model based on experiments that utilized capillary reactors and off-line GC analysis for total flow rates between 6 and 20 mL/min. Thus, it can be assumed that this analytical method is accurate and that ideal plug flow behavior occurs in the microreactor. Performing real-time measurements at various locations in the reactor results in a considerable increase in the experimental throughput. The direct measurements in the reaction channel were combined with a decreasing flow rate to dynamically measure the conversion. As a result, time-series reaction data over nearly the full range of reaction conversions were collected in approximately one-third of the time required for steady-state experiments. Combining this reactor system with a laboratory automation system would enable the rapid screening of reaction parameters to find the optimal conditions in a minimal amount of time with minimal reactant consumption.

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S.S. and F.B. contributed equally to the experimental work.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00184. F



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