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ArticleNovember 3, 2023

Impact of Flow Configurations on Response Time and Data Quality in Real-Time, In-Line Fourier Transform Infrared (FTIR) Monitoring of Viscous Flows
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Nasser Al Azri
Nasser Al Azri
Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, Pennsylvania 15261, United States
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https://orcid.org/0000-0003-3873-2592
Corey Clifford
Corey Clifford
Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, Pennsylvania 15261, United States
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Robert M. Enick
Robert M. Enick
Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, Pennsylvania 15261, United States
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https://orcid.org/0000-0003-1801-8033
Götz Veser*
Götz Veser
Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, Pennsylvania 15261, United States
*Email: [email protected]
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https://orcid.org/0000-0002-2084-4636

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Organic Process Research & Development

Cite this: Org. Process Res. Dev. 2024, 28, 5, 1657–1667

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https://doi.org/10.1021/acs.oprd.3c00299

Published November 3, 2023

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Abstract

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The real-time, in-line monitoring of continuous flow concentrations is widely conducted via infrared (IR) spectrometry by using a flow cell connected to a reactive flow stream. For protective purposes, the IR sensor tip is typically offset from the flow. This offset can cause the formation of a stagnant boundary layer above the sensor, especially when dealing with high-viscosity fluids. As a result, the IR signal response time is often controlled by the slow diffusional exchange of fluid in the boundary layer, as confirmed via 2D computational fluid dynamics (CFD) simulations. We evaluated several flow configuration modifications in a typical IR flow cell in order to identify the changes to the flow dynamics that enable improved response times with minimal changes to the cell configuration: the use of (i) vertical flow, where the standard horizontal flow over the sensor is redirected to contact vertically with the sensor, (ii) a static mixer to create radial flow momentum above the IR sensor, and (iii) horizontal or vertical nozzles to direct the flow toward the IR sensor. The vertical flow configuration did not show any significant improvement over the standard horizontal flow configuration. However, the static mixer, horizontal nozzle, and vertical nozzle configurations all resulted in markedly improved response times and signal quality, albeit at the expense of a higher pressure drop across the flow cell. These results point toward straightforward, user-accessible modifications of in-line IR flow cells that result in significant improvements in signal stability and acquisition times.

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SPECIAL ISSUE

This article is part of the Flow Chemistry Enabling Efficient Synthesis 2024 special issue.

1. Introduction

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The real-time, in-line monitoring of reactant and/or product concentrations in a reactive continuous flow is widely used both in research and developmental laboratories, as well as in the chemical industry. (1−3) It is typically achieved via a flow cell or a probe sensor that is connected or inserted into the flow stream. This in-line monitoring enables one to reliably analyze complex reaction systems and gain a better understanding of and better control over chemical processes with minimal flow intervention and without the need for disruptive and invasive sampling and off-line analysis. (4−6) From a safety perspective, it allows one to detect and monitor hazardous chemicals with minimal contact (7) and accurately manage process safety under continuous flow conditions. (8,9) In addition, the in-line monitoring of the progress of a reaction is becoming even more important in the context of intensifying specialty and fine chemicals processing by transitioning from batch operations to continuous operations. (10−12) This batch-to-continuous transition requires a continuous in-line tracking of concentrations in order to perform rapid screening of reaction conditions, (13−16) identify key intermediate steps and reaction end points, (17,18) and develop robust and sensitive reaction kinetics and thermodynamic data (19−22) that can be used for process modeling, design, optimization, and scale-up of continuous flow processes.

The real-time, in-line monitoring of reactive continuous flows has been demonstrated using different spectroscopic tools such as Raman spectroscopy, (23−25) nuclear magnetic resonance (NMR) spectroscopy, (26,27) mass spectroscopy (MS), (28,29) ultraviolet–visible (UV–vis) spectroscopy, (30,31) high-performance liquid chromatography (HPLC), (32,33) near-infrared (NIR) spectroscopy, (34,35) and Fourier transform infrared (FTIR) spectroscopy. (36−38) Raman spectroscopy, NMR spectroscopy, and MS allow for the qualitative and quantitative study of the chemical composition (i.e., structure, concentration, product yield, and reaction rates) with a high time efficiency due to the high resolution and speed of the data acquisition processes. However, these spectroscopic tools remain comparatively difficult to use for in-line monitoring when studying complex reaction mixtures, as these techniques are often compromised by signal-overlapping. (39) UV–vis spectroscopy measures the ability of a chemical substance to absorb light in the ultraviolet and visible regions of the electromagnetic spectrum. Thus, it is limited to UV–vis-active compounds and lacks the ability to obtain any structural information. (39−41) FTIR spectroscopy enables the qualitative and quantitative study of the chemical composition by identifying and tracing functional groups in (typically organic) compounds over time based on their unique vibrational spectra in the IR range with high specificity and good temporal resolution. For this reason, FTIR is the most widely used in-line analytical tool in continuous flow chemistry when applied to specialty and fine chemicals, as these chemicals are usually identified by specific functional groups. (42,43)

In order to monitor the reactive flow in a continuous flow reactor, the IR probe sensor is typically contained in a flow cell connected in-line or at the exit of the reactor. (44,45) Within this cell, the IR sensor tip is typically offset from the continuous horizontal flow for protective purposes. Here, we focus on the Mettler Toledo ReactIR flow cell, a widely used commercial IR instrument with a typical flow cell configuration, in which the IR sensor tip is offset by 1 mm from the flow path. While this configuration is well-suited for medium- or low-viscosity fluids, high-viscosity flows with viscosities of up to several thousand centipoises, which are often encountered in specialty and fine chemistry, result in very low Reynolds numbers (Re < 10) and, hence, a (near) stagnant boundary layer above the sensor that updates very slowly. This can result in strong delays in response times to changes in the flow composition caused by transient reaction conditions or by changes in the experimental conditions (such as flow rate or temperature), resulting in excessively long experimental run times, the consumption of large amounts of raw materials, and uncertainty and inaccuracy in the measurements. To address this issue, in this study we present a combined experimental–computational evaluation of several flow cell configurations with the goal of accelerating response times by using simple modifications of the flow cell that the user can implement to achieve significant improvements in response time and IR signal stability.

2. Experimental Section

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2.1. IR Instrument

The present study utilized a ReactIR 45m instrument (Mettler Toledo), which is a Fourier transform infrared (FTIR) spectrometer designed for the real-time, in-line monitoring of reaction components. The instrument was fitted with a 24 h mercury cadmium telluride (MCT) detector and coupled with a diamond-tipped attenuated total reflectance (ATR) sentinel sensor (DiComp) and a K4 mirror conduit. (45) The diamond sentinel sensor was located inside a flow cell with a cylindrical channel (internal diameter = 4.82 mm) that could be connected to a reaction flow stream for continuous in-line monitoring over a range of temperatures (193–473 K) and pressures (vacuum up to 103 bar) (Figure 1).

Figure 1. Standard horizontal flow configuration, where the IR sensor tip (red) that is located inside the flow cell (gray) is offset by 1 mm from the horizontal flow channel.

2.2. Investigated Flow Path Configurations

To identify the effects of flow dynamics on the temporal response of the infrared (IR) system, five different flow configurations in the flow cell were experimentally investigated, as shown in Figure 2: (A) the commercial standard horizontal flow (HF) configuration, where the flow enters from one side, passes through a cylindrical channel, and exits from the opposite side. (B) A static mixer (SM) configuration, where a helical static mixer (Stratos Tube Mixer, Koflo, Part No. 3/16-17) with an outer diameter (OD) of 4.82 mm, an internal diameter (ID) of 3.35 mm, a length (L) of 12.38 cm, and 17 helical elements was inserted into the flow cell channel to transfer a radial flow momentum and direct the stream toward the IR sensor window. (C) A horizontal nozzle (HN) configuration, where a 1 mm homemade nozzle (made from a Swagelok tube with an OD of 3.18 mm) was inserted horizontally into the flow channel to directly impinge the flow downward onto the IR sensor window. (D) A vertical nozzle (VN) configuration, in which a 1.75 mm homemade nozzle (made from a Swagelok tube with an OD of 4.76 mm) was inserted vertically into the flow channel to direct a vertically impinging flow toward the IR sensor window. Finally, (E) a vertical flow (VF) configuration, where the standard flow was simply redirected from a horizontal to a vertical contact with the IR sensor window (i.e., without the use of a nozzle).

Figure 2. The five flow configurations investigated in the present study: (A) standard horizontal flow (HF), (B) static mixer (SM), (C) horizontal nozzle (HN), (D) vertical nozzle (VN), and (E) vertical flow (VF).

2.3. Continuous Flow Setup

A simplified schematic of the continuous flow setup is shown in Figure 3. A positive displacement pump (Tuthill) was used to continuously feed the solvent or polymer–solvent mixture; a three-way valve was used for rapid switching between the two feeds. The volumetric flow rate of the feed was monitored via a flow meter, which was used to maintain the desired feed flow rate through the system. For all of the experiments reported in this study, the flow was laminar with a Reynolds number Re < 10. An in-line ReactIR 45m spectrometer was used to monitor the IR signal versus time. The volume between the three-way valve and the IR sensor was ∼42 cm³, resulting in an expected initial delay in the IR signal between 126 s for a flow rate of 20 cm³/s and 13 s for a flow rate of 200 cm³/s. A thermocouple probe and pressure transducers were used to continuously monitor the inlet fluid temperature and pressure drop across the flow cell, respectively, for the different flow configurations (monitored via LabVIEW).

Figure 3. Flow diagram of the continuous flow setup.

2.4. Experimental Flow Mixtures

To evaluate the impact of viscosity on the response time and data quality for the different flow configurations, seven different samples were prepared with different viscosities by varying the amount of solvent (mineral oil or petroleum naphtha) and polymer (polyisobutylene succinic anhydride (PIBSA) with a molecular weight of ∼1000, which is completely miscible with both solvents), as shown in Table 1. In this fashion, the viscosity of the flow (at 293 K) was adjusted from 7 to 4850 mPa s (i.e., by almost 3 orders of magnitude) without changing the chemical nature of the polymer–solvent mixture. Sample S1 (pure petroleum naphtha) was used to investigate the time it took to replace the S2 and S3 polymer–solvent mixtures (i.e., to remove them from the IR sensor tip), while sample S4 (pure mineral oil) was used to replace the high-viscosity polymer–solvent mixtures S5–S7. The mineral oil that was used was a hydrotreated heavy paraffinic petroleum distillate mixture of C₂₀ to C₃₁ saturated hydrocarbon isomers. The petroleum naphtha that was used was a hydrotreated light petroleum distillate mixture of C₈ to C₁₉ nonaromatics, monoaromatics, and diaromatics derived from the refining of crude oil. All chemicals (mineral oil, petroleum naphtha, and PIBSA) were provided by the Lubrizol Corporation and were used as obtained.

Table 1. Compositions and Physical Properties at Room Temperature (293 K) of the Experimental Mixtures Used in the Present Study^a

	solvent wt %
sample identifier	mineral oil	petroleum naphtha	polymer wt %	viscosity at 293 K (mPa s)	density at 293 K (kg/m³)
S1	-	100%	0%	7	780
S2	-	80%	20%	9	802
S3	-	60%	40%	28	826
S4	100%	-	0%	42	840
S5	80%	-	20%	134	852
S6	60%	-	40%	769	865
S7	40%	-	60%	4850	879

^{^a}

The mixtures cover a wide range of fluid viscosities and are labeled in order of viscosity, from the least viscous sample (S1) to most viscous sample (S7). All experiments were conducted at room temperature.

2.5. Infrared (IR) Signal Analysis

The IR signal response was monitored by evaluating the changes in the peak area versus time while switching from a pure solvent (S1 or S4) to a polymer–solvent mixture (S2, S3, S5, S6, or S7) and vice versa. The polymer–solvent mixtures had a clearly identifiable signal between 1831 and 1738 cm^–1, corresponding to the carbonyl group (C═O) of polyisobutylene succinic anhydride (PIBSA), while the pure solvents had no signal in this range, allowing for robust tracing of the change in the flow composition (Figure 4). For quantification, the full peak area of the carbonyl group (C═O) was selected with a two-point baseline correction and traced every 5 s. The obtained peak area time trace was converted to a normalized anhydride concentration signal by using eq 1. A normalized signal of 0 indicates the pure solvent, while a normalized signal of 1 indicates the presence of the polymer–solvent mixture at the IR sensor. The reproducibility of the IR signal response was investigated (Figure S1); it was determined that the signals were closely reproducible with a maximum standard error of 0.14 for the horizontal nozzle, 0.13 for the vertical nozzle, and 0.09 for the static mixer.

normalized anhydride signal = \frac{C═O peak area (t) - C═O peak area (\min)}{C═O peak area (\max) - C═O peak area (\min)}

(1)

Figure 4. IR spectra of the solvent (dashed line) and polymer–solvent mixtures (solid lines). The polymer–solvent mixtures have a distinct peak between 1831 and 1738 cm^–1, corresponding to the carbonyl group (C═O) of the polymer.

2.6. Computational Fluid Dynamics (CFD)

To gain further insight into the experimentally observed effects of the flow cell geometry on the temporal response of the IR sensor, two-dimensional (2D) computational fluid dynamics (CFD) simulations were performed (using Ansys Fluent, version 2021R2) (46) and validated against the corresponding experimental observations. Coupled mass, linear momentum, and species conservation relationships (eqs 2–4) were applied to the flow cell configurations shown in Figure 2 to assess the impacts of the resultant velocity profiles, boundary layers, and possible dead volume on the response time at the IR sensor. Assuming that the pure solvent and polymer–solvent mixture hydraulically behave as a single mixture, the conservation expressions take the following form:

\frac{\partial ρ}{\partial t} + \nabla \cdot (ρ \vec{v}) = 0

(2)

\frac{\partial}{\partial t} (ρ \vec{v}) + \nabla \cdot (ρ \vec{v} \times \vec{v}) = - \nabla p + \nabla \cdot [μ (\nabla \vec{v} + {(\nabla \vec{v})}^{T})] + ρ \vec{g}

(3)

\frac{\partial}{\partial t} (ρ Y_{i}) + \nabla \cdot (ρ \vec{v} Y_{i}) = \nabla \cdot (ρ D_{i,m} \nabla Y_{i})

(4)

where ρ is the fluid density, v⃗ is the velocity vector, p is the local pressure, μ is the dynamic viscosity, g⃗ is the gravitational acceleration field, Y_i is the mass fraction of the ith species, and D_i,m is the corresponding mass diffusivity of that species within the mixture. Each simulated flow cell was assumed to be isothermal (i.e., no temperature-induced variations in the thermophysical properties of each species) by using the densities and dynamic viscosities listed in Table 1. The local material properties were computed using the mass-weighted average (based on the mass fraction of the species) of the constitutive chemicals within each finite volume cell.

For each flow cell configuration, a structured orthogonal mesh was generated by dividing the 2D geometry into quadrilaterals (see Figure S2 for an example of the decomposition of the HF configuration) and specifying the number of divisions across each edge. To capture any dead volume around the IR sensor, an additional grading operation was specified to bias the local mesh size down to 0.1 μm at the surface of the sensor. It should be noted that, to ensure a sufficient spatial resolution in the CFD results, this grid spacing was significantly smaller than the penetration depth (i.e., sampling depth) of the IR beam ∼2 μm above the sensor tip. An example of this mesh grading on the HF flow cell is displayed in Figure S3. The grid independence in the obtained computational results was verified by successively refining the finite volume mesh until the solution remained invariant to increases in the cell density.

Within each simulation, a laminar flow model was used (as Re < 10 for all experiments) in conjunction with the following boundary conditions: (i) a fixed uniform inlet velocity, (ii) zero diffusion flux for all flow variables (i.e., outflow boundary condition) to model the flow at the cell exit, and (iii) no-slip conditions at the wall. The inlet velocity was calculated by using each of the experimental volumetric flow rates and the cross-sectional area of the inlet channel or nozzle of the flow cell. Second-order accurate numerical schemes were applied to the temporal, advection, and diffusion terms in eqs 2–4. All three conservation equations were iterated until the root-mean-square residuals fell below an absolute convergence criterion of 1 × 10^–6. To initialize the transient simulations, a steady-state simulation was performed first and used as the initial condition for the respective transient runs. At each inlet flow rate, the applied Δt was successively decreased until a time-step invariant solution was obtained.

3. Results and Discussion

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3.1. Infrared (IR) Signal Response to Flow Changes Using Different Configurations

To evaluate how the IR signal responded to changes in the flow composition for the different flow configurations, experimental studies were performed by initially flowing pure solvent through the flow cell channel and then switching to a polymer–solvent mixture (i.e., switching from a less viscous to a more viscous flow). Figure 5 shows the normalized anhydride signal time traces when switching from the S4 solvent to the S5 polymer–solvent mixture for the five investigated flow path configurations: horizontal flow (black dotted line), horizontal nozzle (solid red line), static mixer (solid green line), vertical flow (magenta dotted line), and vertical nozzle (solid blue line) at flow rates of 20 cm³/min (Figure 5A), 100 cm³/min (Figure 5B), and 200 cm³/min (Figure 5C), respectively.

Figure 5. IR signal (shown here as the normalized anhydride signal) vs time when switching from the S4 solvent (viscosity = 42 mPa s) to the S5 polymer–solvent mixture (viscosity = 134 mPa s) at flow rates of (A) 20, (B) 100, and (C) 200 cm³/min (note the different time scales for the x-axis).

The time t = 0 min represents the time when the three-way valve was switched from S4 to S5; thus, the initial time delay in the IR signal is due to the flow volume between the three-way valve and the IR sensor, as described in section 2.3. The time delays in both the horizontal flow (HF) and vertical flow (VF) configurations extend significantly beyond the expected initial delay at each flow rate (Figure 5, black and magenta dotted lines, respectively). Additionally, the time to full “signal conversion” (i.e., the detection of the full polymer–solvent mixture signal at the IR sensor with a normalized anhydride signal of 1) for these two flow configurations is the longest out of all the configurations. In addition to this extended initial delay and long amount of time to achieve full signal conversion, the IR signal is unstable, and the time trace does not follow a smooth “S-shaped” transition, which is particularly pronounced at a lower flow rate.

Utilizing a static mixer (SM) to break up the boundary layer characteristic of the fully developed laminar flow and hence improve the radial mixing at the IR sensor resulted in a significantly improved response time, with a shortened initial delay time and a shorter time to achieve full signal conversion, as well as the stabilization of the acquired signal (Figure 5, green line). Impinging the flow directly onto the IR sensor tip using the two nozzle configurations (horizontal nozzle (HN) and vertical nozzle (VN)) resulted in an even further acceleration of the fluid exchange at the IR sensor and, hence, the shortest delay and response times, which were again most visible at lower flow rates (see the red and blue lines in Figure 5 for HN and VN, respectively).

Similar effects were observed when switching from more viscous to less viscous flows (see Figure 6 for the case when the flow switched from the S5 polymer–solvent mixture to the S4 solvent). For the horizontal and vertical flow configurations, the delay time in the IR signal drastically increased beyond the expected initial time delay, especially at the lowest flow rate when these configurations became essentially unusable, and the time to achieve full signal conversion (i.e., the detection of the pure solvent signal at the IR sensor with a normalized signal of 0) also further increased. Considering the switch from low- to high-viscosity flows discussed above, the IR signal also showed poor stability (indicating flow instabilities). These issues became even more pronounced when the change in viscosity was larger (e.g., switching between S4 and S6, which increased the viscosity of the flow by almost 20-fold; see Figures S4 and S5).

Figure 6. IR signal (shown here as the normalized anhydride signal) vs time when switching from the S5 polymer–solvent mixture (viscosity = 134 mPa s) to the S4 solvent (viscosity = 42 mPa s) at flow rates of (A) 20, (B) 100, and (C) 200 cm³/min (note the different time scales for the x-axis).

These results show that the standard horizontal flow and the vertical flow configurations are unsuitable for high-viscosity flows. We hypothesized that the offset of the IR sensor from the continuous flow path caused the liquid volume above the IR sensor to form a stagnant boundary layer, which limited the fluid exchange in the critical measurement area. To verify this hypothesis, we conducted detailed CFD simulations, as described in the following section.

3.2. 2D Computational Fluid Dynamics (CFD) Simulations

To gain deeper insights into the fluid flow dynamics, computational fluid dynamics (CFD) models of the steady-state velocity profiles in the flow cell channel were developed using the S5 polymer–solvent mixture for three of the flow configurations: the (i) horizontal flow configuration (Figure 7), (ii) vertical flow configuration (Figure 8), and (iii) horizontal nozzle configuration (Figure 9) with a flow rate of 20 cm³/min, which corresponds to inlet velocities of 0.0182 m/s for the horizontal and vertical flow configurations and 0.1382 m/s for the horizontal nozzle configuration. Similar steady-state velocity profiles were also developed for these flow configurations with a flow rate of 200 cm³/min (Figure S6).

Figure 7. Steady-state velocity profile developed using CFD for the horizontal flow configuration using the physical properties of the S5 polymer–solvent mixture and an inlet flow rate of 20 cm³/min.

Figure 8. Steady-state velocity profile developed using CFD for the vertical flow configuration using the physical properties of the S5 polymer–solvent mixture and an inlet flow rate of 20 cm³/min.

Figure 9. Steady-state velocity profile developed using CFD for the horizontal nozzle configuration using the physical properties of the S5 polymer–solvent mixture and an inlet flow rate of 20 cm³/min.

For the horizontal and vertical flow configurations, the steady-state models show a velocity of 0 (blue) and a thick, stagnant boundary layer in the fluid volume right above the IR sensor tip. These results indicate that the fluid exchange in the critical measurement area of the IR sensor (up to 2 μm above the sensor tip) is purely diffusion-driven, thus explaining the long initial time delay and the long time to full conversion that were observed experimentally (Figures 5 and 6). At higher flow rates (i.e., higher velocities), the fluid exchange becomes faster due to the higher shear rate, which shortens the time to full signal conversion. In contrast, the horizontal nozzle configuration forces the flow to impinge onto the IR sensor window, as indicated by the area with a non-zero velocity profile (green-yellow) in the fluid volume right above the IR sensor.

Next, transient CFD simulations were performed to investigate the time needed for a pure solvent to replace a polymer–solvent mixture in the IR sensor measurement area and to gain further insight into the impact of diffusive mass transfer on the concentrations in the boundary layer. A critical parameter that is required for the CFD species transport models is the mass diffusivity. To the best of our knowledge, there is no reported literature value of the mass diffusion coefficient D_{oil–polymer} of mineral oil in polyisobutylene succinic anhydride. Therefore, the experimentally measured normalized time traces were used to fit the diffusion coefficient (D_{oil–polymer}) based on the set of experiments where S6 was replaced with S4 at flow rates of 20, 100, and 200 cm³/min. A diffusion coefficient (D_{oil–polymer}) between 1.0 × 10^–14 and 5.0 × 10^–14 m²/s resulted in a reasonable fit (Figure S7), and these values were used to compare the simulated time traces to the experimental data when replacing the S5 polymer–solvent mixture with the S4 solvent at flow rates of 20, 100, and 200 cm³/min (Figure 10). A reasonable agreement was observed, with the maximum time differences between the experimental data and the simulations not exceeding ∼10%, i.e., 3 min for the lowest flow rate (20 cm³/min) and 0.4 min for the highest flow rate (200 cm³/min). This confirms that the very slow diffusion-driven fluid exchange due to the offset of the IR window from the flow path renders the horizontal and vertical flow configurations as poorly suited for viscous flows because of the formation of a stagnant boundary layer.

Figure 10. Comparing the transient behavior between the CFD simulations and the experimental data for the horizontal flow configuration when switching from the S5 polymer–solvent mixture to the S4 solvent at flow rates of (A) 20, (B) 100, and (C) 200 cm³/min. The light-blue shaded area represents the error band for the experimental time traces (based on our experimental data reproducibility tests).

3.3. Effect of Fluid Viscosity on Infrared (IR) Signal Response Time

Because the standard horizontal flow configuration was identified as being poorly suited for highly viscous flows, we next aimed to identify the viscosity range for which this configuration shows an acceptable performance (i.e., rapid response times and stable signals). Therefore, IR signal time traces were investigated when switching from polymer–solvent mixtures with different viscosities to a pure solvent at flow rates of 20 and 100 cm³/min (the vertical flow configuration was not further investigated, as it had shown no significant improvement over the standard horizontal flow configuration). Figure 11 summarizes the results using plots of the response time (Δt) versus viscosity of the polymer–solvent mixture, where response time is defined as the time it takes to obtain a normalized signal of 0.05 after switching from the polymer–solvent mixture to the pure solvent. This time difference includes the initial delay time due to the flow volume between the three-way valve and the IR sensor.

Figure 11. Response time (Δt) to go from a normalized signal of 1 to 0.05 when switching from polymer–solvent mixtures with different viscosities to a pure solvent at flow rates of (A) 20 and (B) 100 cm³/min (note the different time scales for the y-axis).

Out of all of the configurations, the horizontal nozzle configuration resulted in the fastest response time (lowest Δt) across the entire range of viscosities studied. The vertical nozzle configuration showed similar behavior at lower viscosities, but at the lower flow rate of 20 cm³/min, its response time strongly increased at the highest viscosity (∼4800 mPa s) from <4 to 32 min. This unexpected behavior can be explained by the geometry of this configuration (Figure 2): the vertical nozzle configuration has dead volume between the walls of the vertical flow tube and the inserted pipe/nozzle. Thus, the solvent “jet” first sweeps the viscous polymer mixture from the IR sensor, as reflected in the rapid drop in the normalized anhydride signal in Figure 12 (blue line). However, due to the extreme viscous nature of S7, the dead volume slowly gets entrained with the pure solvent flow, resulting in the subsequent increase in the normalized signal. Once the dead volume is cleared, the signal resumes the expected drop to zero, albeit still with some instability/disruption due to small amounts of residual polymer in the dead volume. Similar behavior was observed for the horizontal nozzle configuration, as the dead volume between the walls of the horizontal path and the inserted pipe causes similar issues (Figure 12, red line); however, clearing the dead volume in this configuration takes slightly less time. This behavior is observed only for the highest-viscosity mixture (S7). Thus, for high-viscosity mixtures, achieving convective flow toward the IR sensor and avoiding dead volume are key for achieving rapid response times.

Figure 12. IR signal response time traces when switching from the S7 polymer–solvent mixture to the S4 solvent at a flow rate of 20 cm³/min for the horizontal nozzle (red line), vertical nozzle (blue line), and static mixer (green line) configurations, highlighting the effect of dead volume on the IR signal acquisition (the right figure is a zoomed-in version of the first 5 min of the left figure (the red shaded area)).

The static mixer configuration showed comparable performance to the vertical and horizontal nozzle configurations at higher flow rates (100 cm³/min), as their response times were almost the same in the range of viscosities investigated in this study (Figure 11B). However, the static mixer configuration was not as good as the nozzle configurations at low flow rates (∼20 cm³/min), having almost double the response time except at the highest viscosity (∼4800 mPa s), where the static mixer configuration showed comparable performance to the vertical nozzle configuration (Figure 11A). In terms of flow stability, the static mixer configuration outperformed both of the nozzle configurations, as it showed an expected “S-shaped” transition, which indicates the absence of the dead volume that was observed with the nozzle configurations (Figure 12, green line). Additionally, it is apparent that the horizontal flow configuration is poorly suited even for fluids with moderately low viscosities (∼10 mPa s) and low flow rates, as its response times are 3 times as long as those of the vertical and horizontal nozzle configurations. However, the standard horizontal configuration seems to be well-suited for higher flow rates (100 cm³/min) and very low viscosities (<10 mPa s), having response times that are comparable to those of the vertical and horizontal nozzle configurations.

3.4. Pressure Drop across the Flow Cell

While the static mixer as well as the horizontal and vertical nozzle configurations show much faster response times that enable accelerated data collection, the downside of these configurations is an increased pressure drop, as shown in Figure 13. For the horizontal and vertical nozzle configurations, pressure drops of up to ∼550 and ∼450 kPa, respectively, were obtained for the highest-viscosity polymer–solvent mixture at a flow rate 20 cm³/min. The static mixer configuration caused a significantly lower pressure drop (∼275 kPa) at the same flow rate; however, this pressure drop was still significantly higher than that of the horizontal flow configuration, which caused a negligible pressure drop. Thus, improved performance in terms of response time and signal quality was achieved at the expense of a higher pressure drop across the flow cell. Given that the static mixer configuration enables response times that are comparable to those of the nozzle configurations with about half the pressure drop, this configuration may be the best compromise for many experimental situations that deal with high-viscosity fluids.

Figure 13. Pressure drop across the flow cell for the different configurations at flow rates of (A) 20 and (B) 100 cm³/min.

4. Conclusion

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In-line FTIR spectrometry is widely used in research and in the industrial monitoring of continuous flows, as it enables real-time, in-line monitoring without the need for sampling and off-line analysis. It is also particularly well-suited for rapidly screening complex reaction systems and their intermediates, identifying reaction mechanisms and kinetics, detecting hazardous chemicals with minimal contact, and monitoring and controlling chemical processes. However, the probe sensor inside in-line flow cells is typically slightly offset from the flow for protective purposes. This offset causes the liquid volume above the IR sensor to form a stagnant boundary layer, especially when dealing with high-viscosity flows. Our investigation sheds light on the slow response times that are often observed with such systems and possible ways to accelerate data acquisition and improve data quality and stability without necessitating a complete redesign of the flow cell.

Our results confirm that the slow response of the typical standard configuration is indeed caused by a purely diffusion-driven fluid exchange in the boundary layer, which was further confirmed via 2D CFD simulations of the fluid flow inside the flow cell. Several alternative flow configurations were evaluated in order to identify the changes to the flow dynamics that enable much faster response times with minimal changes to the instrumental configuration: a vertical flow configuration that redirects the standard horizontal flow toward vertical contact with the IR sensor; a static mixer configuration that introduces a helical static mixer in the horizontal flow channel to create radial flow momentum above the IR sensor; and two nozzle configurations (vertical and horizontal nozzles) that utilize a smaller-diameter pipe inside the inlet channel to force flow impingement on the IR sensor. The overall observations are summarized qualitatively in Table 2. It was determined that the vertical flow configuration does not yield a significant improvement over the standard horizontal flow configuration. In contrast, the static mixer, horizontal nozzle, and vertical nozzle configurations resulted in significant improvements in response times and signal quality, albeit at the expense of a higher pressure drop, especially when using the nozzle configurations.

Table 2. Summary of the Experimental Data for the Different Flow Configurations with Ratings: Good (+), Moderate (o), and Poor (−)^a

	horizontal flow (HF)	vertical flow (VF)	static mixer (SM)	horizontal nozzle (HN)	vertical nozzle (VN)
IR sensor signal response	–	–	o	+	+
data reproducibility	–	–	+	+	+
pressure drop	+	+	o	–	–

^{^a}

In regard to the IR sensor signal response, data reproducibility, and pressure drop of the flow configurations, (+) indicates a fast response time, good data reproducibility, and a low pressure drop, respectively, while (−) indicates a slow response time, poor data reproducibility, and a high pressure drop, respectively. (o) represents moderate/medium values for all aspects.

Overall, our study shows that simple, user-accessible modifications to typical in-line IR sampling can achieve significant improvements in data acquisition (i.e., response times and signal stability) when dealing with high-viscosity flows without the need for a complete redesign of the flow cell configuration. These modifications reduce experimental run times, reduce the amount of raw materials required for kinetic experimentations, and improve the reliability of in-line IR measurements. Thus, such modifications should be valuable to a wide range of chemists and chemical engineers who use in-line IR spectrometry in their work.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.3c00299.

The reproducibility of the experimentally measured IR signal response for the three most efficient configurations, the structured orthogonal mesh details used for the CFD simulations, supporting data for the IR signal response for different mixtures, supporting data for the steady-state velocity profile and transient behavior of the normalized IR signal using CFD, and plots of experimentally measured temperatures and flow rates versus time for two different cases (PDF)

op3c00299_si_001.pdf (1.22 MB)

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Author Information

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Corresponding Author
- Götz Veser - Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, Pennsylvania 15261, United States; https://orcid.org/0000-0002-2084-4636; Email: [email protected]
Authors
- Nasser Al Azri - Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, Pennsylvania 15261, United States; https://orcid.org/0000-0003-3873-2592
- Corey Clifford - Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, Pennsylvania 15261, United States
- Robert M. Enick - Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, Pennsylvania 15261, United States; https://orcid.org/0000-0003-1801-8033
Notes
The authors declare no competing financial interest.

Acknowledgments

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The authors acknowledge the financial support from AIChE RAPID under contract #DEEE0007888-5-8. Additionally, this research was supported in part by the University of Pittsburgh Center for Research Computing through the computational resources provided.

References

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An integrated microchem. system is presented that combines micromixing, a reaction channel, an IR detection region, and temp. control for monitoring and kinetic studies of liq.-phase reactions. The microdevices exploit the transparency of silicon to IR radiation in most of the wavelength region of interest (4000-800 cm-1), the precise definition of microfluidic channels by deep reactive ion-etching, the high thermal cond. of silicon, and the fusion bonding of silicon for fixed-path-length transmission cells. Two devices are considered, a simple T-shaped mixer and an efficient mixer with interleaving channels for rapid mixing. The first device is used to characterize IR transmission characteristics in silicon-based microreactors and to demonstrate the feasibility of monitoring exothermic reactions, the hydrolysis of propionyl chloride under isothermal conditions. The mixing characteristics of the second microreactor are evaluated exptl. by an acid-base reaction and predicted by computational fluid dynamics simulations. Typical mixing times are 25 ms. The alk. hydrolysis of Me formate, a reaction following second-order kinetics with a half-life of 70 ms, exemplifies the use of the microreactor in detg. rate consts. The results demonstrate the main advantages of the integrated microchem. systems in reaction monitoring: faster mixing times, temp. control, in situ detection, and elimination of sample post processing.
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Müller, J. J.; Neumann, M.; Scholl, P.; Hilterhaus, L.; Eckstein, M.; Thum, O.; Liese, A. Online monitoring of biotransformations in high viscous multiphase systems by means of FT-IR and chemometrics. Analytical chemistry 2010, 82 (14), 6008– 6014, DOI: 10.1021/ac100469t
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Online Monitoring of Biotransformations in High Viscous Multiphase Systems by Means of FT-IR and Chemometrics
Mueller, Jakob J.; Neumann, Markus; Scholl, Paul; Hilterhaus, Lutz; Eckstein, Marrit; Thum, Oliver; Liese, Andreas
Analytical Chemistry (Washington, DC, United States) (2010), 82 (14), 6008-6014CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
In unstable emulsion systems, the detn. of concns. is a challenge. The use of std. methods like GC, HPLC, or titrn. is highly inaccurate and makes the acquisition of precise data for these systems complex. In addn., the handicap of high viscosity often comes into play. To overcome these fundamental limitations, the online FT-IR technique was identified in combination with chemometric modeling in order to improve accuracy. The reactor type used in this study is a bubble column reactor with up to four dispersed phases (solid catalyst, two liq. immiscible substrates, and a gaseous phase). The investigated reactions are solvent free enzymic esterifications yielding myristyl myristate (10 mPa s) and high viscous polyglycerol-3-laurate (300-1500 mPa s), representative industrial products for cosmetic applications. For both reactions, chemometric models were successfully set up and reproducibly applied in the prediction of progress curves of a new set of expts. This allows the automated detn. of sensitive kinetic and thermodn. data as well as reaction velocities in high viscous multiphase (bio)chem. systems.
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Mozharov, S.; Nordon, A.; Littlejohn, D.; Wiles, C.; Watts, P.; Dallin, P.; Girkin, J. M. Improved Method for Kinetic Studies in Microreactors Using Flow Manipulation and Noninvasive Raman Spectrometry. J. Am. Chem. Soc. 2011, 133 (10), 3601– 3608, DOI: 10.1021/ja1102234
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Improved Method for Kinetic Studies in Microreactors Using Flow Manipulation and Noninvasive Raman Spectrometry
Mozharov, Sergey; Nordon, Alison; Littlejohn, David; Wiles, Charlotte; Watts, Paul; Dallin, Paul; Girkin, John M.
Journal of the American Chemical Society (2011), 133 (10), 3601-3608CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A novel method has been devised to derive kinetic information about reactions in microfluidic systems. Advantages have been demonstrated over conventional procedures for a Knoevenagel condensation reaction in terms of the time required to obtain the data (fivefold redn.) and the efficient use of reagents (tenfold redn.). The procedure is based on a step change from a low (e.g., 0.6 μL min-1) to a high (e.g., 14 μL min-1) flow rate and real-time noninvasive Raman measurements at the end of the flow line, which allows location-specific information to be obtained without the need to move the measurement probe along the microreactor channel. To validate the method, values of the effective reaction order n were obtained employing two different exptl. methodologies. Using these values of n, rate consts. k were calcd. and compared. The values of k derived from the proposed method at 10 and 40 °C were 0.0356 ± 0.0008 mol-0.3 dm0.9 s-1 (n = 1.3) and 0.24 ± 0.018 mol-0.1 dm0.3 s-1 (n = 1.1), resp., whereas the values obtained using a more laborious conventional methodol. were 0.0335 ± 0.0032 mol-0.4 dm1.2 s-1 (n = 1.4) at 10 °C and 0.244 ± 0.032 mol-0.3 dm0.9 s-1 (n = 1.3) at 40 °C. The new approach is not limited to anal. by Raman spectrometry and can be used with different techniques that can be incorporated into the end of the flow path to provide rapid measurements.
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Ładosz, A.; Kuhnle, C.; Jensen, K. F. Characterization of reaction enthalpy and kinetics in a microscale flow platform. Reaction Chemistry & Engineering 2020, 5 (11), 2115– 2122, DOI: 10.1039/D0RE00304B
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Characterization of reaction enthalpy and kinetics in a microscale flow platform
Ladosz, Agnieszka; Kuhnle, Christina; Jensen, Klavs F.
Reaction Chemistry & Engineering (2020), 5 (11), 2115-2122CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
We report an isothermal flow calorimeter for characterization of reaction enthalpy and kinetics. The platform consists of a thermoelec. element and a glass-silicon microreactor to measure heat flux and an inline IR spectrometer to monitor reaction conversion. The thermally insulated assembly is calibrated with a thin film heater placed between the microreactor and the thermoelec. element. Without any reconfiguration of hardware, the setup can also be used to efficiently characterize reaction kinetics in transient flow expts. We tested the calorimeter with hydrolysis of acetic anhydride as a model reaction. We detd. the exothermic reaction enthalpy and the endothermic heat of mixing of the reagent to be -63 ± 3.0 kJ mol-1 and +8.8 ± 2.1 kJ mol-1 resp., in good agreement with literature values and theor. predictions. Following calorimetry studies, we investigated reaction kinetics by applying carefully controlled residence time ramps at four different temps., and we obtained kinetic rate consts. of 0.129 min-1 up to 0.522 min-1 for temps. between 20°C and 56.3°C, also fitting well with data reported in the literature.
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Hamlin, T. A.; Leadbeater, N. E. Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions. Beilstein journal of organic chemistry 2013, 9 (1), 1843– 1852, DOI: 10.3762/bjoc.9.215
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Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: equipment interface and assessment in four medicinally-relevant reactions
Hamlin, Trevor A.; Leadbeater, Nicholas E.
Beilstein Journal of Organic Chemistry (2013), 9 (), 1843-1852, 10 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
An app. is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability is assessed by studying four reactions, all involving formation of products bearing α,β-unsatd. carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen-Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by means of a calibration curve, det. product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy.
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Fletcher, P. D.; Haswell, S. J.; Zhang, X. Monitoring of chemical reactions within microreactors using an inverted Raman microscopic spectrometer. Electrophoresis 2003, 24 (18), 3239– 3245, DOI: 10.1002/elps.200305532
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Monitoring of chemical reactions within microreactors using an inverted Raman microscopic spectrometer
Fletcher, Paul D. I.; Haswell, Stephen J.; Zhang, Xunli
Electrophoresis (2003), 24 (18), 3239-3245CODEN: ELCTDN; ISSN:0173-0835. (Wiley-VCH Verlag GmbH & Co. KGaA)
An inverted Raman microscope spectrometer was used to profile the spatial evolution of reactant and product concns. for a chem. reaction within a microreactor operating under hydrodynamic flow control. The Raman spectrometer was equipped with a laser source at wavelength of 780 nm, confocal optics, a holog. transmission grating, and a charge-coupled device (CCD) detector. The microreactor consisted of a T-shaped channel network etched within a 0.5 mm thick glass bottom plate that was thermally bonded to a 0.5 mm thick glass top plate. The ends of the channel network were connected to reagent reservoirs that were linked to a syringe pump for driving the solns. by hydrodynamic pumping within the channels. The microchannels were 221 μm wide and 73 μm deep. The synthesis of Et acetate from ethanol and acetic acid was studied as a model system within the microreactor as Raman scattering bands for each reactant and product species were clearly resolved. Raman spectral intensities of each band were proportional to concn. for each species and hence all concns. could be quant. measured after calibration. By scanning specific Raman bands within a selected area in the microchannel network at given steps in the X-Y plane, spatially resolved concn. profiles were obtained under steady-state flow conditions. Under the flow conditions used, different positions within the concn. profile correspond to different times after contact and mixing of the reagents, thereby enabling one to observe the time dependence of the product formation. Raman microscopy provides a useful complementary technique to UV/visible absorbance and fluorescence methods for the in situ monitoring and anal. of chem. reaction species having their lowest S0-S1 absorption bands too far in the UV to be of use, due to their probable overlap with the bands from other reactant, product and solvent mols.
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Chaplain, G.; Haswell, S. J.; Fletcher, P. D.; Kelly, S. M.; Mansfield, A. Development and evaluation of a Raman flow cell for monitoring continuous flow reactions. Aust. J. Chem. 2013, 66 (2), 208– 212, DOI: 10.1071/CH12379
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Development and Evaluation of a Raman Flow Cell for Monitoring Continuous Flow Reactions
Chaplain, Grant; Haswell, Stephen J.; Fletcher, Paul D. I.; Kelly, Stephen M.; Mansfield, Andrew
Australian Journal of Chemistry (2013), 66 (2), 208-212CODEN: AJCHAS; ISSN:0004-9425. (CSIRO Publishing)
In-line Raman spectroscopy can be used to monitor both reactant and product concns. for a heterogeneously catalyzed Suzuki cross reaction operating in continuous flow. The flow system consisted of an HPLC pump to drive a homogeneous mixt. of the reactants (4-bromobenzonitrile, phenylboronic acid, and potassium carbonate) through an oven heated (80°) palladium catalyst immobilized on a silica monolith. A custom built PTFE in-line flow cell with a quartz window enabled the coupling of an Ocean Optics Raman spectrometer probe to monitor both the reactants and product (4-cyanobiphenyl). Calibration was based on obtaining multivariate spectral data in the range 1530 cm-1 and 1640 cm-1 and using partial least-squares regression (PLSR) to obtain a calibration model which was validated using gas chromatog.-mass spectrometry (GCMS) anal. In-line Raman monitoring of the reactant and product concns. enable (i) detn. of reaction kinetic information such as the empirical rate law and assocd. rate const. and (ii) optimization of either the product conversion (61% at 0.02 mL min-1 generating 17 g h-1) or product yield (14% at 0.24 mL min-1 generating 53 g h-1).
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Gökay, O.; Albert, K. From single to multiple microcoil flow probe NMR and related capillary techniques: a review. Anal. Bioanal. Chem. 2012, 402 (2), 647– 669, DOI: 10.1007/s00216-011-5419-z
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From single to multiple microcoil flow probe NMR and related capillary techniques: a review
Gokay Ozan; Albert Klaus
Analytical and bioanalytical chemistry (2012), 402 (2), 647-69 ISSN:.
Nuclear magnetic resonance (NMR) spectroscopy is one of the most important and powerful instrumental analytical techniques for structural elucidation of unknown small and large (complex) isolated and synthesized compounds in organic and inorganic chemistry. X-ray crystallography, neutron scattering (neutron diffraction), and NMR spectroscopy are the only suitable methods for three-dimensional structure determination at atomic resolution. Moreover, these methods are complementary. However, by means of NMR spectroscopy, reaction dynamics and interaction processes can also be investigated. Unfortunately, this technique is very insensitive in comparison with other spectrometric (e.g., mass spectrometry) and spectroscopic (e.g., infrared spectroscopy) methods. Mainly through the development of stronger magnets and more sensitive solenoidal microcoil flow probes, this drawback has been successfully counteracted. Capillary NMR spectroscopy increases the mass-based sensitivity of the NMR spectroscopic analysis up to 100-fold compared with conventional 5-mm NMR probes, and thus can be coupled online and off-line with other microseparation and detection techniques. It offers not only higher sensitivity, but in many cases provides better quality spectra than traditional methods. Owing to the immense number of compounds (e.g., of natural product extracts and compound libraries) to be examined, single microcoil flow probe NMR spectroscopy will soon be far from being sufficiently effective as a screening method. For this reason, an inevitable trend towards coupled microseparation-multiple microcoil flow probe NMR techniques, which allow simultaneous online and off-line detection of several compounds, will occur. In this review we describe the current status and possible future developments of single and multiple microcoil capillary flow probe NMR spectroscopy and its application as a high-throughput tool for the analysis of a large number of mass-limited samples. The advantages and drawbacks of different coupled microseparation-capillary NMR spectroscopy techniques, such as capillary high-performance liquid chromatography-NMR spectroscopy, capillary electrophoresis-NMR spectroscopy, and capillary gas chromatography-NMR spectroscopy, are discussed and demonstrated by specific applications. Another subject of discussion is the progress in parallel NMR detection techniques. Furthermore, the applicability and mixing capability of tiny reactor systems, termed "microreactors" or "micromixers," implemented in NMR probes is demonstrated by carbamate- and imine-forming reactions.
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Jones, C. J.; Larive, C. K. Could smaller really be better? Current and future trends in high-resolution microcoil NMR spectroscopy. Anal. Bioanal. Chem. 2012, 402 (1), 61– 68, DOI: 10.1007/s00216-011-5330-7
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Could smaller really be better? Current and future trends in high-resolution microcoil NMR spectroscopy
Jones, Christopher J.; Larive, Cynthia K.
Analytical and Bioanalytical Chemistry (2012), 402 (1), 61-68CODEN: ABCNBP; ISSN:1618-2642. (Springer)
NMR is an invaluable anal. technique that provides structural and chem. information about a mol. without destroying the sample. However, NMR suffers from an inherent lack of sensitivity compared to other popular anal. techniques. This trends article focuses on strategies to increase the sensitivity of NMR using solenoidal microcoil, microstrip, and microslot probes. The role of these reduced-vol. receiver coils for detection in hyphenated capillary electrophoresis (CE) and capillary isotachophoresis (cITP) NMR expts. is discussed. Future directions will likely build on work to develop probes contg. multiple coils for high-throughput NMR and field-portable instruments.
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Koster, S.; Verpoorte, E. A decade of microfluidic analysis coupled with electrospray mass spectrometry: An overview. Lab Chip 2007, 7 (11), 1394– 1412, DOI: 10.1039/b709706a
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A decade of microfluidic analysis coupled with electrospray mass spectrometry: An overview
Koster, Sander; Verpoorte, Elisabeth
Lab on a Chip (2007), 7 (11), 1394-1412CODEN: LCAHAM; ISSN:1473-0197. (Royal Society of Chemistry)
A review. This review presents a thorough overview covering the period 1997-2006 of microfluidic chips coupled to mass spectrometry through an electrospray interface. The different types of fabrication processes and materials used to fabricate these chips throughout this period are discussed. Three eras' of interfaces are clearly distinguished. The earliest approach involves spraying from the edge of a chip, while later devices either incorporate a std. fused-silica emitter inserted into the device or fully integrated emitters formed during chip fabrication. A summary of microfluidic-electrospray devices for performing sepns. and sample pretreatment steps before sample introduction into the mass spectrometer is also presented.
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Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner, R. M.; Ley, S. V. Continuous flow reaction monitoring using an on-line miniature mass spectrometer. Rapid Commun. Mass Spectrom. 2012, 26 (17), 1999– 2010, DOI: 10.1002/rcm.6312
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Continuous flow reaction monitoring using an on-line miniature mass spectrometer
Browne, Duncan L.; Wright, Steven; Deadman, Benjamin J.; Dunnage, Samantha; Baxendale, Ian R.; Turner, Richard M.; Ley, Steven V.
Rapid Communications in Mass Spectrometry (2012), 26 (17), 1999-2010CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
RATIONALE : A recently developed miniature electrospray ionization mass spectrometer was coupled to a preparative flow chem. system to monitor reactive intermediates and competing reaction paths, screen starting materials, and optimize reaction conditions. Although ideally suited to the application, mass spectrometers have rarely been used in this way, as traditional instruments are too bulky to be conveniently coupled to flow chem. platforms. METHODS : A six-port switching valve fitted with a 5 μL loop was used to periodically sample the flow stream leaving the reactor coil. Mass spectra corresponding to the sample loop contents were obsd. ∼10 s after activating the valve. High fluidic pressure was maintained throughout to ensure that gaseous products remained in soln. As an illustrative example of how this app. can be employed, the generation of benzyne and its subsequent reaction with furan were studied. Benzyne was prepd. via diazotization of anthranilic acid using tert-Bu nitrite. RESULTS : Unexpectedly, the explosive diazotized intermediate was detected by the mass spectrometer at low coil temps. or short residence times. The optimum reactor temp. and residence time for prodn. of the desired Diels-Alder product are 50 °C and 3-5 min, resp. There are competing reaction pathways giving acridone and several other byproducts. CONCLUSIONS : Online mass spectrometry allowed the flow conditions to be quickly tuned for safe operation and optimal generation of the desired product. The validity of this approach was corroborated by off-line liq. chromatog./mass spectrometry (LC/MS) anal. of flow samples. Copyright © 2012 John Wiley and Sons, Ltd.
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Lu, H.; Schmidt, M. A.; Jensen, K. F. Photochemical reactions and on-line UV detection in microfabricated reactors. Lab Chip 2001, 1 (1), 22– 28, DOI: 10.1039/b104037p
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Photochemical reactions and on-line UV detection in microfabricated reactors
Lu, Hang; Schmidt, Martin A.; Jensen, Klavs F.
Lab on a Chip (2001), 1 (1), 22-28CODEN: LCAHAM; ISSN:1473-0197. (Royal Society of Chemistry)
This work presents an application of microfabricated reactors and detectors for photochem. reactions. Two fabrication schemes were demonstrated for the integration of the reaction and the detection modules: coupling individually packaged chips, and monolithic integration of the two functions. In the latter fabrication scheme, the authors have succeeded in bonding quartz wafers to patterned silicon wafers at low temp. using a Teflon-like polymer-CYTOP. Using quartz substrates allows reaction and detection with UV light of lower wavelengths than Pyrex substrates permit. The pinacol formation reaction of benzophenone in isopropanol was the model reaction to demonstrate the performance of the microreactors. The extent of reaction was controlled by varying the flow rate and therefore the on-chip residence time. Crystn. of the product inside the microreactors was avoided by the continuous-flow design. Instead, crystn. was obsd. in the effluent storage device. Off-chip anal. using HPLC confirms the results obtained from the online UV spectroscopy. The quantum yield estd. suggests that the reactor design is effective in improving the overall efficiency of the reactor unit.
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Benito-Lopez, F.; Verboom, W.; Kakuta, M.; Gardeniers, J. H. G.; Egberink, R. J.; Oosterbroek, E. R.; van den Berg, A.; Reinhoudt, D. N. Optical fiber-based on-line UV/Vis spectroscopic monitoring of chemical reaction kinetics under high pressure in a capillary microreactor. Chem. Commun. 2005, 22, 2857– 2859, DOI: 10.1039/b500429b
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McMullen, J. P.; Stone, M. T.; Buchwald, S. L.; Jensen, K. F. An Integrated Microreactor System for Self-Optimization of a Heck Reaction: From Micro- to Mesoscale Flow Systems. Angew. Chem., Int. Ed. 2010, 49 (39), 7076– 7080, DOI: 10.1002/anie.201002590
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An Integrated Microreactor System for Self-Optimization of a Heck Reaction: from Micro- to Mesoscale Flow Systems
McMullen, Jonathan P.; Stone, Matthew T.; Buchwald, Stephen L.; Jensen, Klavs F.
Angewandte Chemie, International Edition (2010), 49 (39), 7076-7080, S7076/1-S7076/13CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A self-optimizing microreactor system is described that employs a black-box optimization technique directed by the J. A. Nelder and R. Mead (1965) simplex method. The system was shown to maximize the yield of a Heck reaction by adjusting the equiv. of the alkene and the residence time. Upon obtaining optimized conditions in a microreactor, the reaction was scaled-up 50-fold in a mesoscale flow reactor. Reaction conditions were surveyed in the mesoscale reactor and found to be in good agreement with the yields obsd. in the microreactor. The optimal residence time and equiv. of alkene were then allowed to run in the mesoscale reactor for 22 reactor vols. (ca. 2 h) and upon purifn. the resulting isolated yield was found to be in good agreement with the online HPLC anal. The Heck reaction of 4-chlorobenzotrifluoride and 2,3-dihydrofuran is chosen for the examn. since the desired product readily reacts with a second equiv. of the aryl chloride. Thus, the yield of the reaction is highly dependent upon the no. of equiv. of 2.
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Greene, J. F.; Preger, Y.; Stahl, S. S.; Root, T. W. PTFE-membrane flow reactor for aerobic oxidation reactions and its application to alcohol oxidation. Org. Process Res. Dev. 2015, 19 (7), 858– 864, DOI: 10.1021/acs.oprd.5b00125
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PTFE-Membrane Flow Reactor for Aerobic Oxidation Reactions and Its Application to Alcohol Oxidation
Greene, Jodie F.; Preger, Yuliya; Stahl, Shannon S.; Root, Thatcher W.
Organic Process Research & Development (2015), 19 (7), 858-864CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
A "tube-in-shell" membrane flow reactor has been developed for aerobic oxidn. reactions that permits continuous delivery of O2 to a liq.-phase reaction along the entire length of the flow path. The reactor uses inexpensive O2-permeable PTFE ("Teflon") tubing that is compatible with elevated pressures and temps. and avoids hazardous mixts. of org. vapor and oxygen. Several polymeric materials were tested, and PTFE exhibits a useful combination of low cost, chem. stability and gas diffusion properties. Reactor performance is demonstrated in the aerobic oxidn. of several alcs. with homogeneous Cu/TEMPO and Cu/ABNO catalysts (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl and ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl). Kinetic studies demonstrate regimes where the overall rate is controlled by the kinetics of the reaction or the transport of oxygen through the tube wall. Near-quant. product yields are achieved with residence times as low as 1 min. A parallel, multitube reactor enables higher throughput, while retaining good performance. Finally, the reactor is demonstrated with a heterogeneous Ru(OH)x/Al2O3 catalyst packed in the tubing.
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Galaverna, R.; Ribessi, R. L.; Rohwedder, J. J. R.; Pastre, J. C. Coupling Continuous Flow Microreactors to MicroNIR Spectroscopy: Ultracompact Device for Facile In-Line Reaction Monitoring. Org. Process Res. Dev. 2018, 22 (7), 780– 788, DOI: 10.1021/acs.oprd.8b00060
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Coupling Continuous Flow Microreactors to MicroNIR Spectroscopy: Ultracompact Device for Facile In-Line Reaction Monitoring
Galaverna, Renan; Ribessi, Rafael L.; Rohwedder, Jarbas J. R.; Pastre, Julio C.
Organic Process Research & Development (2018), 22 (7), 780-788CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
In this study, we applied a portable near-IR spectrophotometer (MicroNIR) for in-line monitoring of the synthesis of 5-hydroxymethylfurfural (5-HMF) in a continuous flow microreactor. Under the best reaction conditions using iso-Pr alc./dimethyl sulfoxide as the reaction solvent and a fixed-bed reactor packed with solid acid catalyst, total conversion of D-fructose was obsd., and 5-HMF was obtained in 95% yield with a residence time of just 11.2 min. Principal component analyses and construction of multivariate control charts based on Hotelling's T2 and Q residuals were also performed and proved the excellent response of the compact MicroNIR device for in-line monitoring of 5-HMF prodn. without variation in the yield over 8 h/day during 5 days. Our results demonstrate the great potential for the application of this compact device in the monitoring of lab.-scale reactions, which can be extended to industrial scales.
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Chablani, L.; Taylor, M. K.; Mehrotra, A.; Rameas, P.; Stagner, W. C. Inline real-time near-infrared granule moisture measurements of a continuous granulation–drying–milling process. Aaps PharmSciTech 2011, 12, 1050– 1055, DOI: 10.1208/s12249-011-9669-z
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Inline Real-Time Near-Infrared Granule Moisture Measurements of a Continuous Granulation-Drying-Milling Process
Chablani, Lipika; Taylor, Michael K.; Mehrotra, Amit; Rameas, Patrick; Stagner, William C.
AAPS PharmSciTech (2011), 12 (4), 1050-1055CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
The purpose of this research was to use inline real-time near-IR (NIR) to measure the moisture content of granules manufd. using a com. prodn. scale continuous twin-screw granulator fluid-bed dryer milling process. A central composite response surface statistical design was used to study the effect of inlet air temp. and dew point on granule moisture content. The NIR moisture content was compared to Karl Fischer (KF) and loss on drying (LOD) moisture detns. Using multivariate anal., the data showed a statistically significant correlation between the conventional methods and NIR. The R 2 values for predicted moisture content by NIR vs. KF and predicted moisture values by NIR vs. LOD were 0.94 (p < 0.00001) and 0.85 (p < 0.0002), resp. The adjusted R 2 for KF vs. LOD correlation was 0.85 (p < 0.0001). Anal. of the response surface design data showed that inlet air temp. over a range of 35-55°C had a significant linear impact on granule moisture content as measured by predicted NIR (adjusted R 2 = 0.84, p < 0.02), KF (adjusted R 2 = 0.91, p < 0.0001), and LOD (adjusted R 2 = 0.85, p < 0.0006). The inlet air dew point range of 10-20°C did not have a significant impact on any of the moisture measurements.
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Kartnaller, V.; Junior, I. I.; de Souza, A. V.; Costa, I. C.; Rezende, M. J.; da Silva, J. F. C.; de Souza, R. O. Evaluating the kinetics of the esterification of oleic acid with homo and heterogeneous catalysts using in-line real-time infrared spectroscopy and partial least squares calibration. Journal of Molecular Catalysis B: Enzymatic 2016, 123, 41– 46, DOI: 10.1016/j.molcatb.2015.09.015
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Evaluating the kinetics of the esterification of oleic acid with homo and heterogeneous catalysts using in-line real-time infrared spectroscopy and partial least squares calibration
Kartnaller, Vinicius; Junior, Ivaldo I.; de Souza, Adriana V. A.; Costa, Ingrid C. R.; Rezende, Michelle J. C.; da Silva, Joao F. Cajaiba; de Souza, Rodrigo O. M. A.
Journal of Molecular Catalysis B: Enzymatic (2016), 123 (), 41-46CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
Biodiesel is a mixt. of fatty acid alkyl esters with properties similar to petroleum-based diesel. Thus, biodiesel can be used as either a substitute for diesel fuel or, more commonly, in a fuel blend. Biodiesel prodn. can be catalyzed with mineral acids or bases or enzymes. The use of real-time techniques for monitoring the reaction and evaluating the efficiency of the catalyst can be of great use for optimizing the reaction and monitoring the process. In the present work, an in-line real-time methodol. was used to evaluate and compare the kinetics of a reaction catalyzed with homo (hydrochloric acid) and heterogeneous (the enzymes Novozym 435, Lipozyme RM, and Lipozyme TL) catalysts. The esterification of oleic acid with ethanol was used as the reaction model. The study used attenuated total reflexion/Fourier transform IR (ATR/FT-IR) and a single partial least squares (PLS) regression model to evaluate the kinetics of the various catalysts, without multiple calibrations, with validation by GC-MS. Novozym 435, which showed complete conversion after 165 min, was the best catalyst for this reaction. Lipozyme RM and Lipozyme TL had inferior conversion after the same amt. of time, in agreement with the literature. All enzymic catalysts showed higher conversion than hydrochloric acid at the same reaction conditions.
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Rueping, M.; Bootwicha, T.; Sugiono, E. Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis. Beilstein journal of organic chemistry 2012, 8 (1), 300– 307, DOI: 10.3762/bjoc.8.32
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Continuous-flow catalytic asymmetric hydrogenations: reaction optimization using FTIR in-line analysis
Rueping, Magnus; Bootwicha, Teerawut; Sugiono, Erli
Beilstein Journal of Organic Chemistry (2012), 8 (), 300-307, No. 32CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
The asym. organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors has been developed. Reaction monitoring was achieved by using an in-line ReactIR flow cell, which allows fast and convenient optimization of reaction parameters. The redn. reactions proceeded well and the desired products were isolated in high yield and in excellent enantioselectivity. The synthesis of the target compds. was achieved using chiral cyclic phosphates I (R = 9-anthracenyl, 9-phenanthryl) as organocatalysts and Hantzsch dihydropyridines as hydrogen donors.
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Brodmann, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V. Continuous preparation of arylmagnesium reagents in flow with inline IR monitoring. Org. Process Res. Dev. 2012, 16 (5), 1102– 1113, DOI: 10.1021/op200275d
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Continuous Preparation of Arylmagnesium Reagents in Flow with In-line IR Monitoring
Brodmann, Tobias; Koos, Peter; Metzger, Albrecht; Knochel, Paul; Ley, Steven V.
Organic Process Research & Development (2012), 16 (5), 1102-1113CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
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A review. The concept and practices of chem. synthesis are being profoundly transformed toward the development of fully autonomous continuous processes. Crit. to the development of autonomous continuous processes is the efficient monitoring of the reaction compn. and product quality by in-line and online analyses. The in-line/online acquisition of anal. data allows one to monitor at regular intervals the reaction compn., including hazardous or air-sensitive intermediates with the possibility of adapting reaction parameters or interrupting the flow process when a chem. or tech. failure is detected. This review presents the main in-line/online anal. tools that can be integrated into flow reactors for the monitoring of chem. reactions. This contribution is more a guide at the service of synthetic chemists illustrated by selected published examples from leading research labs. than an exhaustive list of published articles. Ultimately, we would like this review to be an answer to the following recurrent, yet complex, question: "Which is/are the most suitable anal. soln.(s) to monitor my chem. reaction ".
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Pirouz, S.; Wang, Y.; Chong, J. M.; Duhamel, J. Chemical modification of polyisobutylene succinimide dispersants and characterization of their associative properties. J. Phys. Chem. B 2015, 119 (37), 12202– 12211, DOI: 10.1021/acs.jpcb.5b04515
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Pirouz, Solmaz; Wang, Yulin; Chong, J. Michael; Duhamel, Jean
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The secondary amines found in b-PIBSI dispersants prepd. by attaching two polyisobutylene chains to a polyamine core via two succinimide moieties were reacted with ethylene carbonate (EC). The reaction generated urethane bonds on the polyamine core to yield the modified b-PIBSI dispersants (Mb-PIBSI). Five dispersants were prepd. by reacting 2 molar equivalent (meq) of polyisobutylene terminated at one end with a succinic anhydride moiety (PIBSA) with 1 meq of hexamethylenediamine (HMDA), diethylenetriamine (DETA), triethylenetetramine (TETA), tetraethylenepentamine (TEPA), and pentaethylenehexamine (PEHA) to yield the corresponding b-PIBSI dispersants. Characterization of the level of secondary amine modification for the Mb-PIBSI dispersants with traditional techniques such as FTIR and 1H NMR spectroscopies was greatly complicated by interactions between the carbonyls of the succinimide groups and unreacted secondary amines of the Mb-PIBSI dispersants. Therefore, an alternative procedure was developed based on fluorescence quenching of the succinimides by secondary amines and urethane groups. The procedure took advantage of the fact that the succinimide fluorescence of the Mb-PIBSI dispersants was quenched much more efficiently by secondary amines than by the urethane groups that resulted from the EC modification of the amines. While EC modification did not proceed for b-PIBSI-DETA and b-PIBSI-TETA certainly due to steric hindrance, 60 and 70% of the secondary amines found in the longer polyamine core of b-PIBSI-TEPA and b-PIBSI-PEHA had reacted with EC as detd. by the fluorescence quenching anal. Furthermore, the ability of the Mb-PIBSI dispersants to adsorb at the surface of carbon black particles used as mimic of the carbonaceous particles typically found in engine oils was compared to that of their unmodified analogs.
44
Miyai, Y.; Formosa, A.; Armstrong, C.; Marquardt, B.; Rogers, L.; Roper, T. PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy. Org. Process Res. Dev. 2021, 25 (12), 2707– 2717, DOI: 10.1021/acs.oprd.1c00299
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PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy
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Organic Process Research & Development (2021), 25 (12), 2707-2717CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
The strategies and exptl. methods for implementation of process anal. technol. (PAT) on the mobile pharmaceutical manufg. system, Pharmacy on Demand (PoD), are discussed. With multiple processes to be monitored on the PoD end-to-end continuous manufg. process, PAT and its real-time process monitoring capability play a significant role in ensuring final product quality. Here, we discuss PAT implementation for real-time monitoring of an intermediate and API concns. with in-line Fourier-transformed IR and Raman spectroscopy for the five-step continuous synthesis of ciprofloxacin on the PoD synthesis unit. Two partial least squares regression models were built and verified with flow chem. expts. to obtain a root-mean-square error of prediction (RMSEP) of 2.2 mg/mL with a relative error of 2.8% for the step 2 FlowIR model and a RMSEP of 0.9 mg/mL with a relative error of 2.8% for the step 5 Raman model. These models were deployed during an 11 h step 1-3 and a 5 h step 4-5 continuous ciprofloxacin synthesis run performed on the PoD system. In these runs, the real-time prediction of intermediate and product concn. was achieved with an online model processing software (Solo_Predictor) and a PAT data collection and management software (synTQ).
45
Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.; Gaunt, N. L. ReactIR flow cell: a new analytical tool for continuous flow chemical processing. Org. Process Res. Dev. 2010, 14 (2), 393– 404, DOI: 10.1021/op900305v
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ReactIR Flow Cell: A new analytical tool for continuous flow chemical processing
Carter, Catherine F.; Lange, Heiko; Ley, Steven V.; Baxendale, Ian R.; Wittkamp, Brian; Goode, Jon G.; Gaunt, Nigel L.
Organic Process Research & Development (2010), 14 (2), 393-404CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
A newly developed ReactIR flow cell is reported as a convenient and versatile inline anal. tool for continuous flow chem. processing. The flow cell, operated with ATR technol., is attached directly into a reaction flow stream using std. OmniFit (HPLC) connections and can be used in combination with both meso- and microscale flow chem. equipment. The iC IR anal. software (version 4.0) enables the monitoring of reagent consumption and product formation, aiding the rapid optimization of procedures. Short-lived reactive intermediates can also be obsd. in situ, giving further mechanistic insight into complex transformations.
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Eva Deitmann, Gabriele Menges-Flanagan, Dirk Ziegenbalg. Infrared Spectroscopy as Process Analytics to Identify and Quantify Grignard Reagents. Organometallics 2024, 43 (3) , 219-226. https://doi.org/10.1021/acs.organomet.3c00441

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Abstract
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Figure 1
Figure 1. Standard horizontal flow configuration, where the IR sensor tip (red) that is located inside the flow cell (gray) is offset by 1 mm from the horizontal flow channel.
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Figure 2
Figure 2. The five flow configurations investigated in the present study: (A) standard horizontal flow (HF), (B) static mixer (SM), (C) horizontal nozzle (HN), (D) vertical nozzle (VN), and (E) vertical flow (VF).
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Figure 3
Figure 3. Flow diagram of the continuous flow setup.
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Figure 4
Figure 4. IR spectra of the solvent (dashed line) and polymer–solvent mixtures (solid lines). The polymer–solvent mixtures have a distinct peak between 1831 and 1738 cm^–1, corresponding to the carbonyl group (C═O) of the polymer.
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Figure 5
Figure 5. IR signal (shown here as the normalized anhydride signal) vs time when switching from the S4 solvent (viscosity = 42 mPa s) to the S5 polymer–solvent mixture (viscosity = 134 mPa s) at flow rates of (A) 20, (B) 100, and (C) 200 cm³/min (note the different time scales for the x-axis).
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Figure 6
Figure 6. IR signal (shown here as the normalized anhydride signal) vs time when switching from the S5 polymer–solvent mixture (viscosity = 134 mPa s) to the S4 solvent (viscosity = 42 mPa s) at flow rates of (A) 20, (B) 100, and (C) 200 cm³/min (note the different time scales for the x-axis).
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Figure 7
Figure 7. Steady-state velocity profile developed using CFD for the horizontal flow configuration using the physical properties of the S5 polymer–solvent mixture and an inlet flow rate of 20 cm³/min.
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Figure 8
Figure 8. Steady-state velocity profile developed using CFD for the vertical flow configuration using the physical properties of the S5 polymer–solvent mixture and an inlet flow rate of 20 cm³/min.
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Figure 9
Figure 9. Steady-state velocity profile developed using CFD for the horizontal nozzle configuration using the physical properties of the S5 polymer–solvent mixture and an inlet flow rate of 20 cm³/min.
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Figure 10
Figure 10. Comparing the transient behavior between the CFD simulations and the experimental data for the horizontal flow configuration when switching from the S5 polymer–solvent mixture to the S4 solvent at flow rates of (A) 20, (B) 100, and (C) 200 cm³/min. The light-blue shaded area represents the error band for the experimental time traces (based on our experimental data reproducibility tests).
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Figure 11
Figure 11. Response time (Δt) to go from a normalized signal of 1 to 0.05 when switching from polymer–solvent mixtures with different viscosities to a pure solvent at flow rates of (A) 20 and (B) 100 cm³/min (note the different time scales for the y-axis).
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Figure 12
Figure 12. IR signal response time traces when switching from the S7 polymer–solvent mixture to the S4 solvent at a flow rate of 20 cm³/min for the horizontal nozzle (red line), vertical nozzle (blue line), and static mixer (green line) configurations, highlighting the effect of dead volume on the IR signal acquisition (the right figure is a zoomed-in version of the first 5 min of the left figure (the red shaded area)).
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Figure 13
Figure 13. Pressure drop across the flow cell for the different configurations at flow rates of (A) 20 and (B) 100 cm³/min.
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References
This article references 46 other publications.
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  Inline near-IR (NIR) spectroscopy has been used to monitor a continuous synthesis of an active pharmaceutical ingredient (API) intermediate by a Grignard alkylation reaction. The reaction between a ketone substrate and allylmagnesium chloride may form significant impurities with excess feeding of the Grignard reagent beyond the stoichiometric ratio. On the other hand, limiting this reagent would imply a loss in yield. Therefore, accurate dosing of the two reactants is essential. A feedforward-feedback control loop was conceived in order to maintain the reaction as closely as possible to the stoichiometric ratio, leading the path to full process automation. The feedback control loop relies on NIR transmission measurements performed in a flow cell where, in contrast to labor-intensive offline HPLC anal. methods, the whole reaction product can be scanned in real time without sample diln. A robust PLS (projection to latent structures) model was developed with a satisfactory std. error of prediction, providing quantification of the ketone substrate in solns. with a high variability of the major soln. component-the alkoxide product. In addn., model performance supervision tools such as the spectral residuals or simple plots of pretreated spectra can assist in the identification of spectral outliers, which in this case could be related to Grignard reagent excess. If the sampling time of the NIR instrument is short enough, manipulating the inputs to the reactor may be used to obtain information about its dynamic behavior. This information is very useful for process control design, assessment of anal. tools and definition of sampling times. In this work, a systematic procedure for chemometric model building is followed, after which a discussion is made on some of the potential applications that can be found when exploiting the fast and rich information provided by NIR spectroscopy.
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10. 10
  Al Azri, N.; Patel, R.; Ozbuyukkaya, G.; Kowall, C.; Cormack, G.; Proust, N.; Enick, R.; Veser, G. Batch-to-Continuous Transition in the Specialty Chemicals Industry: Impact of Operational Differences on the Production of Dispersants. Chemical Engineering Journal 2022, 445, 136775, DOI: 10.1016/j.cej.2022.136775
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  Specialty chems. are typically produced in large-vol. batch reactors characterized by straight-forward operation but limited efficiency. Process intensification via transition from batch to continuous operation offers the prospect of strong improvements over current state-of-the-art in energy intensity, process safety, capital cost, and phys. footprint. The present study investigated the prodn. of two dispersants to demonstrate the viability of batch-to-continuous transition for the specialty chems. industry: Succinate ester dispersants, formed in a one-step addn. reaction, and succinimide dispersants, formed via a two-step reaction with water as a byproduct. While the ester process showed identical dispersant yields in batch and continuous operation under identical conditions, the succinimide process produced significantly higher yields in the batch compared to the continuous reactor. This could be traced back to an operational difference between these processes: In the batch process, the byproduct water is continuously removed from the reactive mixt. while purging the reactor head space, rendering the dehydration step effectively irreversible. In contrast, to prevent steam-induced foaming, the continuous reactor is operated at high-enough pressure to maintain water in the liq. phase. This renders the dehydration step incomplete due to thermodn. equil. limitations. However, the full succinimide product yield could be recovered via subsequent continuous drying using a thin film evaporator. This product was indistinguishable from the batch product and fulfilled com. specifications. Finally, full reversible reaction kinetics were derived based on the continuous reactor operation. Comparison between batch operation results and reactor modeling predictions indicated that the slow apparent kinetics of the industrial batch process is the result of mass transfer limitations due to slow water evapn., and not caused by limitations in the intrinsic reaction kinetics.
11. 11
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  11
  Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor
  Malet-Sanz, Laia; Madrzak, Julia; Ley, Steven V.; Baxendale, Ian R.
  Organic & Biomolecular Chemistry (2010), 8 (23), 5324-5332CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  A flow procedure for the prepn. of arylsulfonyl chlorides from aniline derivs. is described; the reaction is carried out using CuCl2 catalyst in ethylene glycol, SO2 in acetonitrile, benzyltriethylammonium chloride and tert-Bu nitrite (tBuONO). The reaction conditions are mild, requiring no added acid and are amenable to continuous flow processing, in a safe, easily scalable and less labor intensive way than the corresponding batch method.
12. 12
  Kaven, L. F.; Wolff, H. J.; Wille, L.; Wessling, M.; Mitsos, A.; Viell, J. In-line Monitoring of Microgel Synthesis: Flow versus Batch Reactor. Org. Process Res. Dev. 2021, 25 (9), 2039– 2051, DOI: 10.1021/acs.oprd.1c00087
  12
  In-line Monitoring of Microgel Synthesis: Flow versus Batch Reactor
  Kaven, Luise F.; Wolff, Hanna J. M.; Wille, Lukas; Wessling, Matthias; Mitsos, Alexander; Viell, Joern
  Organic Process Research & Development (2021), 25 (9), 2039-2051CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  In-line monitoring of polymn. via Raman spectroscopy is std. for batch reactors but yet to be manifested for flow reactors. When transferring the in-line Raman spectroscopy from batch to flow reactors, the aim is to maintain the measurement precision. We present a customized Raman measurement cell for in-line monitoring in a tubular flow reactor and a systematic accuracy anal. of the obtained measurement. The accuracy anal. involves comparing three calibration models and measurements of flowing solvent, monomer soln., and microgel soln. The evaluation of the measurements reveals that multimol. analyte solns. most significantly influence the quantification accuracy. From these studies, we derive a quality criterion for the Raman measurements based on the root mean square error, and apply the criterion to the monitoring of pptn. polymn. of poly(N-iso-propylacrylamide) (PNIPAM) microgels. The results compare the predictions from the Raman measurements of the microgel synthesis in the flow and batch reactor. Applying the quality criterion enables high-quality measurements and allows the functional detection of outliers during the synthesis. The identification and exclusion of outliers eliminate several potential errors to cause the difference in measurement results from the flow and batch reactors. This contribution serves as a guideline for transferring in-line monitoring from batch to flow reactors as the example of pptn. polymn.
13. 13
  Liu, X.; Ünal, B.; Jensen, K. F. Heterogeneous catalysis with continuous flow microreactors. Catalysis Science & Technology 2012, 2 (10), 2134– 2138, DOI: 10.1039/c2cy20260c
  13
  Heterogeneous catalysis with continuous flow microreactors
  Liu, Xiaoying; Uenal, Baris; Jensen, Klavs F.
  Catalysis Science & Technology (2012), 2 (10), 2134-2138CODEN: CSTAGD; ISSN:2044-4753. (Royal Society of Chemistry)
  Packed-bed microreactors are employed under flow conditions for studies of heterogeneous catalysis: oxidn. of 4-isopropylbenzaldehyde and hydrogenation of 2-methylfuran. They have been demonstrated to be a valuable platform for rapid screening of catalytic materials, efficient optimization of reaction conditions, inline monitoring of reaction progress, and extn. of kinetic parameters.
14. 14
  Sambiagio, C.; Noël, T. Flow photochemistry: Shine some light on those tubes!. Trends in Chemistry 2020, 2 (2), 92– 106, DOI: 10.1016/j.trechm.2019.09.003
  14
  Review on flow photochemistry, shine some light on those tubes
  Sambiagio, Carlo; Noel, Timothy
  Trends in Chemistry (2020), 2 (2), 92-106CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)
  A review. Continuous-flow chem. has recently attracted significant interest from chemists in both academia and industry working in different disciplines and from different backgrounds. Flow methods are now being used in reaction discovery/methodol., in scale-up and prodn., and for rapid screening and optimization. Photochem. processes are currently an important research field in the scientific community and the recent exploitation of flow methods for these methodologies has made clear the advantages of flow chem. and its importance in modern chem. and technol. worldwide. This review highlights the most important features of continuous-flow technol. applied to photochem. processes and provides a general perspective on this rapidly evolving research field.
15. 15
  Noël, T.; Su, Y.; Hessel, V. Beyond organometallic flow chemistry: the principles behind the use of continuous-flow reactors for synthesis. Organometallic Flow Chemistry 2015, 57, 1– 41, DOI: 10.1007/3418_2015_152
  There is no corresponding record for this reference.
16. 16
  Leung, S.-A.; Winkle, R. F.; Wootton, R. C.; Demello, A. J. A method for rapid reaction optimization in continuous-flow microfluidic reactors using online Raman spectroscopic detection. Analyst 2005, 130 (1), 46– 51, DOI: 10.1039/b412069h
  16
  A method for rapid reaction optimisation in continuous-flow microfluidic reactors using online Raman spectroscopic detection
  Leung, Shee-Ann; Winkle, Richard F.; Wootton, Robert C. R.; deMello, Andrew J.
  Analyst (Cambridge, United Kingdom) (2005), 130 (1), 46-51CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
  An extremely rapid tool for continuous flow synthetic process optimization is described. A microfluidic reaction system operating in continuous flow is used in conjunction with confocal Raman microscopy to afford rapid mol. synthesis and product quantitation. Accordingly, the approach allows for rapid reaction optimization within a continuous flow system. Specifically, the catalytic oxidn. of iso-Pr alc. (IPA) to acetone using tetra-N-propylammonium perruthenate (TPAP)/N-methylmorpholine N-oxide (NMO) in a radial interdigitated micromixer is studied as a model reaction system. The compn. of the reaction effluent can be detd. with great facility and information relating to catalyst/co-oxidant ratios, catalyst turnovers and reaction endpoints extd. Specifically, variation of catalyst and co-oxidant volumetric flow rates between 0-50 μL min-1 is used to vary reactant concns., define reaction residence times, and control product conversions between 0-100%. The rapid nature of the system allows chem. information to be gathered and utilized on a sub-minute timescale.
17. 17
  Carter, C. F.; Baxendale, I. R.; O’Brien, M.; Pavey, J. B. J.; Ley, S. V. Synthesis of acetal protected building blocks using flow chemistry with flow I.R. analysis: preparation of butane-2,3-diacetal tartrates. Organic & Biomolecular Chemistry 2009, 7 (22), 4594– 4597, DOI: 10.1039/b917289k
  17
  Synthesis of acetal protected building blocks using flow chemistry with flow I.R. analysis: preparation of butane-2,3-diacetal tartrates
  Carter, Catherine F.; Baxendale, Ian R.; O'Brien, Matthew; Pavey, John B. J.; Ley, Steven V.
  Organic & Biomolecular Chemistry (2009), 7 (22), 4594-4597CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  The syntheses of butane-2,3-diacetal protected tartrate derivs. are described using continuous flow processing techniques with in-line purifn. and I.R. anal. protocols.
18. 18
  Foley, D. A.; Doecke, C. W.; Buser, J. Y.; Merritt, J. M.; Murphy, L.; Kissane, M.; Collins, S. G.; Maguire, A. R.; Kaerner, A. ReactNMR and ReactIR as reaction monitoring and mechanistic elucidation tools: the NCS mediated cascade reaction of α-thioamides to α-thio-β-chloroacrylamides. Journal of organic chemistry 2011, 76 (23), 9630– 9640, DOI: 10.1021/jo201212p
  18
  ReactNMR and ReactIR as Reaction Monitoring and Mechanistic Elucidation Tools: The NCS Mediated Cascade Reaction of α-Thioamides to α-Thio-β-chloroacrylamides
  Foley, David A.; Doecke, Christopher W.; Buser, Jonas Y.; Merritt, Jeremy M.; Murphy, Linda; Kissane, Marie; Collins, Stuart G.; Maguire, Anita R.; Kaerner, Andreas
  Journal of Organic Chemistry (2011), 76 (23), 9630-9640CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  On-flow ReactIR and 1H NMR reaction monitoring, coupled with in situ intermediate characterization, was used to aid in the mechanistic elucidation of the N-chlorosuccinimide mediated transformation of an α-thioamide. Multiple intermediates in this reaction cascade are identified and characterized, and in particular, spectroscopic evidence for the intermediacy of the chlorosulfonium ion in the chlorination of α-thioamides is provided. Further to this, solvent effects on the outcome of the transformation are discussed. This work also demonstrates the utility of using a combination of ReactIR and flow NMR reaction monitoring (ReactNMR) for characterizing complex multicomponent reaction mixts.
19. 19
  Floyd, T. M.; Schmidt, M. A.; Jensen, K. F. Silicon Micromixers with Infrared Detection for Studies of Liquid-Phase Reactions. Ind. Eng. Chem. Res. 2005, 44 (8), 2351– 2358, DOI: 10.1021/ie049348j
  19
  Silicon Micromixers with Infrared Detection for Studies of Liquid-Phase Reactions
  Floyd, Tamara M.; Schmidt, Martin A.; Jensen, Klavs F.
  Industrial & Engineering Chemistry Research (2005), 44 (8), 2351-2358CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)
  An integrated microchem. system is presented that combines micromixing, a reaction channel, an IR detection region, and temp. control for monitoring and kinetic studies of liq.-phase reactions. The microdevices exploit the transparency of silicon to IR radiation in most of the wavelength region of interest (4000-800 cm-1), the precise definition of microfluidic channels by deep reactive ion-etching, the high thermal cond. of silicon, and the fusion bonding of silicon for fixed-path-length transmission cells. Two devices are considered, a simple T-shaped mixer and an efficient mixer with interleaving channels for rapid mixing. The first device is used to characterize IR transmission characteristics in silicon-based microreactors and to demonstrate the feasibility of monitoring exothermic reactions, the hydrolysis of propionyl chloride under isothermal conditions. The mixing characteristics of the second microreactor are evaluated exptl. by an acid-base reaction and predicted by computational fluid dynamics simulations. Typical mixing times are 25 ms. The alk. hydrolysis of Me formate, a reaction following second-order kinetics with a half-life of 70 ms, exemplifies the use of the microreactor in detg. rate consts. The results demonstrate the main advantages of the integrated microchem. systems in reaction monitoring: faster mixing times, temp. control, in situ detection, and elimination of sample post processing.
20. 20
  Müller, J. J.; Neumann, M.; Scholl, P.; Hilterhaus, L.; Eckstein, M.; Thum, O.; Liese, A. Online monitoring of biotransformations in high viscous multiphase systems by means of FT-IR and chemometrics. Analytical chemistry 2010, 82 (14), 6008– 6014, DOI: 10.1021/ac100469t
  20
  Online Monitoring of Biotransformations in High Viscous Multiphase Systems by Means of FT-IR and Chemometrics
  Mueller, Jakob J.; Neumann, Markus; Scholl, Paul; Hilterhaus, Lutz; Eckstein, Marrit; Thum, Oliver; Liese, Andreas
  Analytical Chemistry (Washington, DC, United States) (2010), 82 (14), 6008-6014CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  In unstable emulsion systems, the detn. of concns. is a challenge. The use of std. methods like GC, HPLC, or titrn. is highly inaccurate and makes the acquisition of precise data for these systems complex. In addn., the handicap of high viscosity often comes into play. To overcome these fundamental limitations, the online FT-IR technique was identified in combination with chemometric modeling in order to improve accuracy. The reactor type used in this study is a bubble column reactor with up to four dispersed phases (solid catalyst, two liq. immiscible substrates, and a gaseous phase). The investigated reactions are solvent free enzymic esterifications yielding myristyl myristate (10 mPa s) and high viscous polyglycerol-3-laurate (300-1500 mPa s), representative industrial products for cosmetic applications. For both reactions, chemometric models were successfully set up and reproducibly applied in the prediction of progress curves of a new set of expts. This allows the automated detn. of sensitive kinetic and thermodn. data as well as reaction velocities in high viscous multiphase (bio)chem. systems.
21. 21
  Mozharov, S.; Nordon, A.; Littlejohn, D.; Wiles, C.; Watts, P.; Dallin, P.; Girkin, J. M. Improved Method for Kinetic Studies in Microreactors Using Flow Manipulation and Noninvasive Raman Spectrometry. J. Am. Chem. Soc. 2011, 133 (10), 3601– 3608, DOI: 10.1021/ja1102234
  21
  Improved Method for Kinetic Studies in Microreactors Using Flow Manipulation and Noninvasive Raman Spectrometry
  Mozharov, Sergey; Nordon, Alison; Littlejohn, David; Wiles, Charlotte; Watts, Paul; Dallin, Paul; Girkin, John M.
  Journal of the American Chemical Society (2011), 133 (10), 3601-3608CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A novel method has been devised to derive kinetic information about reactions in microfluidic systems. Advantages have been demonstrated over conventional procedures for a Knoevenagel condensation reaction in terms of the time required to obtain the data (fivefold redn.) and the efficient use of reagents (tenfold redn.). The procedure is based on a step change from a low (e.g., 0.6 μL min-1) to a high (e.g., 14 μL min-1) flow rate and real-time noninvasive Raman measurements at the end of the flow line, which allows location-specific information to be obtained without the need to move the measurement probe along the microreactor channel. To validate the method, values of the effective reaction order n were obtained employing two different exptl. methodologies. Using these values of n, rate consts. k were calcd. and compared. The values of k derived from the proposed method at 10 and 40 °C were 0.0356 ± 0.0008 mol-0.3 dm0.9 s-1 (n = 1.3) and 0.24 ± 0.018 mol-0.1 dm0.3 s-1 (n = 1.1), resp., whereas the values obtained using a more laborious conventional methodol. were 0.0335 ± 0.0032 mol-0.4 dm1.2 s-1 (n = 1.4) at 10 °C and 0.244 ± 0.032 mol-0.3 dm0.9 s-1 (n = 1.3) at 40 °C. The new approach is not limited to anal. by Raman spectrometry and can be used with different techniques that can be incorporated into the end of the flow path to provide rapid measurements.
22. 22
  Ładosz, A.; Kuhnle, C.; Jensen, K. F. Characterization of reaction enthalpy and kinetics in a microscale flow platform. Reaction Chemistry & Engineering 2020, 5 (11), 2115– 2122, DOI: 10.1039/D0RE00304B
  22
  Characterization of reaction enthalpy and kinetics in a microscale flow platform
  Ladosz, Agnieszka; Kuhnle, Christina; Jensen, Klavs F.
  Reaction Chemistry & Engineering (2020), 5 (11), 2115-2122CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
  We report an isothermal flow calorimeter for characterization of reaction enthalpy and kinetics. The platform consists of a thermoelec. element and a glass-silicon microreactor to measure heat flux and an inline IR spectrometer to monitor reaction conversion. The thermally insulated assembly is calibrated with a thin film heater placed between the microreactor and the thermoelec. element. Without any reconfiguration of hardware, the setup can also be used to efficiently characterize reaction kinetics in transient flow expts. We tested the calorimeter with hydrolysis of acetic anhydride as a model reaction. We detd. the exothermic reaction enthalpy and the endothermic heat of mixing of the reagent to be -63 ± 3.0 kJ mol-1 and +8.8 ± 2.1 kJ mol-1 resp., in good agreement with literature values and theor. predictions. Following calorimetry studies, we investigated reaction kinetics by applying carefully controlled residence time ramps at four different temps., and we obtained kinetic rate consts. of 0.129 min-1 up to 0.522 min-1 for temps. between 20°C and 56.3°C, also fitting well with data reported in the literature.
23. 23
  Hamlin, T. A.; Leadbeater, N. E. Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions. Beilstein journal of organic chemistry 2013, 9 (1), 1843– 1852, DOI: 10.3762/bjoc.9.215
  23
  Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: equipment interface and assessment in four medicinally-relevant reactions
  Hamlin, Trevor A.; Leadbeater, Nicholas E.
  Beilstein Journal of Organic Chemistry (2013), 9 (), 1843-1852, 10 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  An app. is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability is assessed by studying four reactions, all involving formation of products bearing α,β-unsatd. carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen-Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by means of a calibration curve, det. product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy.
24. 24
  Fletcher, P. D.; Haswell, S. J.; Zhang, X. Monitoring of chemical reactions within microreactors using an inverted Raman microscopic spectrometer. Electrophoresis 2003, 24 (18), 3239– 3245, DOI: 10.1002/elps.200305532
  24
  Monitoring of chemical reactions within microreactors using an inverted Raman microscopic spectrometer
  Fletcher, Paul D. I.; Haswell, Stephen J.; Zhang, Xunli
  Electrophoresis (2003), 24 (18), 3239-3245CODEN: ELCTDN; ISSN:0173-0835. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An inverted Raman microscope spectrometer was used to profile the spatial evolution of reactant and product concns. for a chem. reaction within a microreactor operating under hydrodynamic flow control. The Raman spectrometer was equipped with a laser source at wavelength of 780 nm, confocal optics, a holog. transmission grating, and a charge-coupled device (CCD) detector. The microreactor consisted of a T-shaped channel network etched within a 0.5 mm thick glass bottom plate that was thermally bonded to a 0.5 mm thick glass top plate. The ends of the channel network were connected to reagent reservoirs that were linked to a syringe pump for driving the solns. by hydrodynamic pumping within the channels. The microchannels were 221 μm wide and 73 μm deep. The synthesis of Et acetate from ethanol and acetic acid was studied as a model system within the microreactor as Raman scattering bands for each reactant and product species were clearly resolved. Raman spectral intensities of each band were proportional to concn. for each species and hence all concns. could be quant. measured after calibration. By scanning specific Raman bands within a selected area in the microchannel network at given steps in the X-Y plane, spatially resolved concn. profiles were obtained under steady-state flow conditions. Under the flow conditions used, different positions within the concn. profile correspond to different times after contact and mixing of the reagents, thereby enabling one to observe the time dependence of the product formation. Raman microscopy provides a useful complementary technique to UV/visible absorbance and fluorescence methods for the in situ monitoring and anal. of chem. reaction species having their lowest S0-S1 absorption bands too far in the UV to be of use, due to their probable overlap with the bands from other reactant, product and solvent mols.
25. 25
  Chaplain, G.; Haswell, S. J.; Fletcher, P. D.; Kelly, S. M.; Mansfield, A. Development and evaluation of a Raman flow cell for monitoring continuous flow reactions. Aust. J. Chem. 2013, 66 (2), 208– 212, DOI: 10.1071/CH12379
  25
  Development and Evaluation of a Raman Flow Cell for Monitoring Continuous Flow Reactions
  Chaplain, Grant; Haswell, Stephen J.; Fletcher, Paul D. I.; Kelly, Stephen M.; Mansfield, Andrew
  Australian Journal of Chemistry (2013), 66 (2), 208-212CODEN: AJCHAS; ISSN:0004-9425. (CSIRO Publishing)
  In-line Raman spectroscopy can be used to monitor both reactant and product concns. for a heterogeneously catalyzed Suzuki cross reaction operating in continuous flow. The flow system consisted of an HPLC pump to drive a homogeneous mixt. of the reactants (4-bromobenzonitrile, phenylboronic acid, and potassium carbonate) through an oven heated (80°) palladium catalyst immobilized on a silica monolith. A custom built PTFE in-line flow cell with a quartz window enabled the coupling of an Ocean Optics Raman spectrometer probe to monitor both the reactants and product (4-cyanobiphenyl). Calibration was based on obtaining multivariate spectral data in the range 1530 cm-1 and 1640 cm-1 and using partial least-squares regression (PLSR) to obtain a calibration model which was validated using gas chromatog.-mass spectrometry (GCMS) anal. In-line Raman monitoring of the reactant and product concns. enable (i) detn. of reaction kinetic information such as the empirical rate law and assocd. rate const. and (ii) optimization of either the product conversion (61% at 0.02 mL min-1 generating 17 g h-1) or product yield (14% at 0.24 mL min-1 generating 53 g h-1).
26. 26
  Gökay, O.; Albert, K. From single to multiple microcoil flow probe NMR and related capillary techniques: a review. Anal. Bioanal. Chem. 2012, 402 (2), 647– 669, DOI: 10.1007/s00216-011-5419-z
  26
  From single to multiple microcoil flow probe NMR and related capillary techniques: a review
  Gokay Ozan; Albert Klaus
  Analytical and bioanalytical chemistry (2012), 402 (2), 647-69 ISSN:.
  Nuclear magnetic resonance (NMR) spectroscopy is one of the most important and powerful instrumental analytical techniques for structural elucidation of unknown small and large (complex) isolated and synthesized compounds in organic and inorganic chemistry. X-ray crystallography, neutron scattering (neutron diffraction), and NMR spectroscopy are the only suitable methods for three-dimensional structure determination at atomic resolution. Moreover, these methods are complementary. However, by means of NMR spectroscopy, reaction dynamics and interaction processes can also be investigated. Unfortunately, this technique is very insensitive in comparison with other spectrometric (e.g., mass spectrometry) and spectroscopic (e.g., infrared spectroscopy) methods. Mainly through the development of stronger magnets and more sensitive solenoidal microcoil flow probes, this drawback has been successfully counteracted. Capillary NMR spectroscopy increases the mass-based sensitivity of the NMR spectroscopic analysis up to 100-fold compared with conventional 5-mm NMR probes, and thus can be coupled online and off-line with other microseparation and detection techniques. It offers not only higher sensitivity, but in many cases provides better quality spectra than traditional methods. Owing to the immense number of compounds (e.g., of natural product extracts and compound libraries) to be examined, single microcoil flow probe NMR spectroscopy will soon be far from being sufficiently effective as a screening method. For this reason, an inevitable trend towards coupled microseparation-multiple microcoil flow probe NMR techniques, which allow simultaneous online and off-line detection of several compounds, will occur. In this review we describe the current status and possible future developments of single and multiple microcoil capillary flow probe NMR spectroscopy and its application as a high-throughput tool for the analysis of a large number of mass-limited samples. The advantages and drawbacks of different coupled microseparation-capillary NMR spectroscopy techniques, such as capillary high-performance liquid chromatography-NMR spectroscopy, capillary electrophoresis-NMR spectroscopy, and capillary gas chromatography-NMR spectroscopy, are discussed and demonstrated by specific applications. Another subject of discussion is the progress in parallel NMR detection techniques. Furthermore, the applicability and mixing capability of tiny reactor systems, termed "microreactors" or "micromixers," implemented in NMR probes is demonstrated by carbamate- and imine-forming reactions.
27. 27
  Jones, C. J.; Larive, C. K. Could smaller really be better? Current and future trends in high-resolution microcoil NMR spectroscopy. Anal. Bioanal. Chem. 2012, 402 (1), 61– 68, DOI: 10.1007/s00216-011-5330-7
  27
  Could smaller really be better? Current and future trends in high-resolution microcoil NMR spectroscopy
  Jones, Christopher J.; Larive, Cynthia K.
  Analytical and Bioanalytical Chemistry (2012), 402 (1), 61-68CODEN: ABCNBP; ISSN:1618-2642. (Springer)
  NMR is an invaluable anal. technique that provides structural and chem. information about a mol. without destroying the sample. However, NMR suffers from an inherent lack of sensitivity compared to other popular anal. techniques. This trends article focuses on strategies to increase the sensitivity of NMR using solenoidal microcoil, microstrip, and microslot probes. The role of these reduced-vol. receiver coils for detection in hyphenated capillary electrophoresis (CE) and capillary isotachophoresis (cITP) NMR expts. is discussed. Future directions will likely build on work to develop probes contg. multiple coils for high-throughput NMR and field-portable instruments.
28. 28
  Koster, S.; Verpoorte, E. A decade of microfluidic analysis coupled with electrospray mass spectrometry: An overview. Lab Chip 2007, 7 (11), 1394– 1412, DOI: 10.1039/b709706a
  28
  A decade of microfluidic analysis coupled with electrospray mass spectrometry: An overview
  Koster, Sander; Verpoorte, Elisabeth
  Lab on a Chip (2007), 7 (11), 1394-1412CODEN: LCAHAM; ISSN:1473-0197. (Royal Society of Chemistry)
  A review. This review presents a thorough overview covering the period 1997-2006 of microfluidic chips coupled to mass spectrometry through an electrospray interface. The different types of fabrication processes and materials used to fabricate these chips throughout this period are discussed. Three eras' of interfaces are clearly distinguished. The earliest approach involves spraying from the edge of a chip, while later devices either incorporate a std. fused-silica emitter inserted into the device or fully integrated emitters formed during chip fabrication. A summary of microfluidic-electrospray devices for performing sepns. and sample pretreatment steps before sample introduction into the mass spectrometer is also presented.
29. 29
  Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner, R. M.; Ley, S. V. Continuous flow reaction monitoring using an on-line miniature mass spectrometer. Rapid Commun. Mass Spectrom. 2012, 26 (17), 1999– 2010, DOI: 10.1002/rcm.6312
  29
  Continuous flow reaction monitoring using an on-line miniature mass spectrometer
  Browne, Duncan L.; Wright, Steven; Deadman, Benjamin J.; Dunnage, Samantha; Baxendale, Ian R.; Turner, Richard M.; Ley, Steven V.
  Rapid Communications in Mass Spectrometry (2012), 26 (17), 1999-2010CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
  RATIONALE : A recently developed miniature electrospray ionization mass spectrometer was coupled to a preparative flow chem. system to monitor reactive intermediates and competing reaction paths, screen starting materials, and optimize reaction conditions. Although ideally suited to the application, mass spectrometers have rarely been used in this way, as traditional instruments are too bulky to be conveniently coupled to flow chem. platforms. METHODS : A six-port switching valve fitted with a 5 μL loop was used to periodically sample the flow stream leaving the reactor coil. Mass spectra corresponding to the sample loop contents were obsd. ∼10 s after activating the valve. High fluidic pressure was maintained throughout to ensure that gaseous products remained in soln. As an illustrative example of how this app. can be employed, the generation of benzyne and its subsequent reaction with furan were studied. Benzyne was prepd. via diazotization of anthranilic acid using tert-Bu nitrite. RESULTS : Unexpectedly, the explosive diazotized intermediate was detected by the mass spectrometer at low coil temps. or short residence times. The optimum reactor temp. and residence time for prodn. of the desired Diels-Alder product are 50 °C and 3-5 min, resp. There are competing reaction pathways giving acridone and several other byproducts. CONCLUSIONS : Online mass spectrometry allowed the flow conditions to be quickly tuned for safe operation and optimal generation of the desired product. The validity of this approach was corroborated by off-line liq. chromatog./mass spectrometry (LC/MS) anal. of flow samples. Copyright © 2012 John Wiley and Sons, Ltd.
30. 30
  Lu, H.; Schmidt, M. A.; Jensen, K. F. Photochemical reactions and on-line UV detection in microfabricated reactors. Lab Chip 2001, 1 (1), 22– 28, DOI: 10.1039/b104037p
  30
  Photochemical reactions and on-line UV detection in microfabricated reactors
  Lu, Hang; Schmidt, Martin A.; Jensen, Klavs F.
  Lab on a Chip (2001), 1 (1), 22-28CODEN: LCAHAM; ISSN:1473-0197. (Royal Society of Chemistry)
  This work presents an application of microfabricated reactors and detectors for photochem. reactions. Two fabrication schemes were demonstrated for the integration of the reaction and the detection modules: coupling individually packaged chips, and monolithic integration of the two functions. In the latter fabrication scheme, the authors have succeeded in bonding quartz wafers to patterned silicon wafers at low temp. using a Teflon-like polymer-CYTOP. Using quartz substrates allows reaction and detection with UV light of lower wavelengths than Pyrex substrates permit. The pinacol formation reaction of benzophenone in isopropanol was the model reaction to demonstrate the performance of the microreactors. The extent of reaction was controlled by varying the flow rate and therefore the on-chip residence time. Crystn. of the product inside the microreactors was avoided by the continuous-flow design. Instead, crystn. was obsd. in the effluent storage device. Off-chip anal. using HPLC confirms the results obtained from the online UV spectroscopy. The quantum yield estd. suggests that the reactor design is effective in improving the overall efficiency of the reactor unit.
31. 31
  Benito-Lopez, F.; Verboom, W.; Kakuta, M.; Gardeniers, J. H. G.; Egberink, R. J.; Oosterbroek, E. R.; van den Berg, A.; Reinhoudt, D. N. Optical fiber-based on-line UV/Vis spectroscopic monitoring of chemical reaction kinetics under high pressure in a capillary microreactor. Chem. Commun. 2005, 22, 2857– 2859, DOI: 10.1039/b500429b
  There is no corresponding record for this reference.
32. 32
  McMullen, J. P.; Stone, M. T.; Buchwald, S. L.; Jensen, K. F. An Integrated Microreactor System for Self-Optimization of a Heck Reaction: From Micro- to Mesoscale Flow Systems. Angew. Chem., Int. Ed. 2010, 49 (39), 7076– 7080, DOI: 10.1002/anie.201002590
  32
  An Integrated Microreactor System for Self-Optimization of a Heck Reaction: from Micro- to Mesoscale Flow Systems
  McMullen, Jonathan P.; Stone, Matthew T.; Buchwald, Stephen L.; Jensen, Klavs F.
  Angewandte Chemie, International Edition (2010), 49 (39), 7076-7080, S7076/1-S7076/13CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A self-optimizing microreactor system is described that employs a black-box optimization technique directed by the J. A. Nelder and R. Mead (1965) simplex method. The system was shown to maximize the yield of a Heck reaction by adjusting the equiv. of the alkene and the residence time. Upon obtaining optimized conditions in a microreactor, the reaction was scaled-up 50-fold in a mesoscale flow reactor. Reaction conditions were surveyed in the mesoscale reactor and found to be in good agreement with the yields obsd. in the microreactor. The optimal residence time and equiv. of alkene were then allowed to run in the mesoscale reactor for 22 reactor vols. (ca. 2 h) and upon purifn. the resulting isolated yield was found to be in good agreement with the online HPLC anal. The Heck reaction of 4-chlorobenzotrifluoride and 2,3-dihydrofuran is chosen for the examn. since the desired product readily reacts with a second equiv. of the aryl chloride. Thus, the yield of the reaction is highly dependent upon the no. of equiv. of 2.
33. 33
  Greene, J. F.; Preger, Y.; Stahl, S. S.; Root, T. W. PTFE-membrane flow reactor for aerobic oxidation reactions and its application to alcohol oxidation. Org. Process Res. Dev. 2015, 19 (7), 858– 864, DOI: 10.1021/acs.oprd.5b00125
  33
  PTFE-Membrane Flow Reactor for Aerobic Oxidation Reactions and Its Application to Alcohol Oxidation
  Greene, Jodie F.; Preger, Yuliya; Stahl, Shannon S.; Root, Thatcher W.
  Organic Process Research & Development (2015), 19 (7), 858-864CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  A "tube-in-shell" membrane flow reactor has been developed for aerobic oxidn. reactions that permits continuous delivery of O2 to a liq.-phase reaction along the entire length of the flow path. The reactor uses inexpensive O2-permeable PTFE ("Teflon") tubing that is compatible with elevated pressures and temps. and avoids hazardous mixts. of org. vapor and oxygen. Several polymeric materials were tested, and PTFE exhibits a useful combination of low cost, chem. stability and gas diffusion properties. Reactor performance is demonstrated in the aerobic oxidn. of several alcs. with homogeneous Cu/TEMPO and Cu/ABNO catalysts (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl and ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl). Kinetic studies demonstrate regimes where the overall rate is controlled by the kinetics of the reaction or the transport of oxygen through the tube wall. Near-quant. product yields are achieved with residence times as low as 1 min. A parallel, multitube reactor enables higher throughput, while retaining good performance. Finally, the reactor is demonstrated with a heterogeneous Ru(OH)x/Al2O3 catalyst packed in the tubing.
34. 34
  Galaverna, R.; Ribessi, R. L.; Rohwedder, J. J. R.; Pastre, J. C. Coupling Continuous Flow Microreactors to MicroNIR Spectroscopy: Ultracompact Device for Facile In-Line Reaction Monitoring. Org. Process Res. Dev. 2018, 22 (7), 780– 788, DOI: 10.1021/acs.oprd.8b00060
  34
  Coupling Continuous Flow Microreactors to MicroNIR Spectroscopy: Ultracompact Device for Facile In-Line Reaction Monitoring
  Galaverna, Renan; Ribessi, Rafael L.; Rohwedder, Jarbas J. R.; Pastre, Julio C.
  Organic Process Research & Development (2018), 22 (7), 780-788CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  In this study, we applied a portable near-IR spectrophotometer (MicroNIR) for in-line monitoring of the synthesis of 5-hydroxymethylfurfural (5-HMF) in a continuous flow microreactor. Under the best reaction conditions using iso-Pr alc./dimethyl sulfoxide as the reaction solvent and a fixed-bed reactor packed with solid acid catalyst, total conversion of D-fructose was obsd., and 5-HMF was obtained in 95% yield with a residence time of just 11.2 min. Principal component analyses and construction of multivariate control charts based on Hotelling's T2 and Q residuals were also performed and proved the excellent response of the compact MicroNIR device for in-line monitoring of 5-HMF prodn. without variation in the yield over 8 h/day during 5 days. Our results demonstrate the great potential for the application of this compact device in the monitoring of lab.-scale reactions, which can be extended to industrial scales.
35. 35
  Chablani, L.; Taylor, M. K.; Mehrotra, A.; Rameas, P.; Stagner, W. C. Inline real-time near-infrared granule moisture measurements of a continuous granulation–drying–milling process. Aaps PharmSciTech 2011, 12, 1050– 1055, DOI: 10.1208/s12249-011-9669-z
  35
  Inline Real-Time Near-Infrared Granule Moisture Measurements of a Continuous Granulation-Drying-Milling Process
  Chablani, Lipika; Taylor, Michael K.; Mehrotra, Amit; Rameas, Patrick; Stagner, William C.
  AAPS PharmSciTech (2011), 12 (4), 1050-1055CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
  The purpose of this research was to use inline real-time near-IR (NIR) to measure the moisture content of granules manufd. using a com. prodn. scale continuous twin-screw granulator fluid-bed dryer milling process. A central composite response surface statistical design was used to study the effect of inlet air temp. and dew point on granule moisture content. The NIR moisture content was compared to Karl Fischer (KF) and loss on drying (LOD) moisture detns. Using multivariate anal., the data showed a statistically significant correlation between the conventional methods and NIR. The R 2 values for predicted moisture content by NIR vs. KF and predicted moisture values by NIR vs. LOD were 0.94 (p < 0.00001) and 0.85 (p < 0.0002), resp. The adjusted R 2 for KF vs. LOD correlation was 0.85 (p < 0.0001). Anal. of the response surface design data showed that inlet air temp. over a range of 35-55°C had a significant linear impact on granule moisture content as measured by predicted NIR (adjusted R 2 = 0.84, p < 0.02), KF (adjusted R 2 = 0.91, p < 0.0001), and LOD (adjusted R 2 = 0.85, p < 0.0006). The inlet air dew point range of 10-20°C did not have a significant impact on any of the moisture measurements.
36. 36
  Kartnaller, V.; Junior, I. I.; de Souza, A. V.; Costa, I. C.; Rezende, M. J.; da Silva, J. F. C.; de Souza, R. O. Evaluating the kinetics of the esterification of oleic acid with homo and heterogeneous catalysts using in-line real-time infrared spectroscopy and partial least squares calibration. Journal of Molecular Catalysis B: Enzymatic 2016, 123, 41– 46, DOI: 10.1016/j.molcatb.2015.09.015
  36
  Evaluating the kinetics of the esterification of oleic acid with homo and heterogeneous catalysts using in-line real-time infrared spectroscopy and partial least squares calibration
  Kartnaller, Vinicius; Junior, Ivaldo I.; de Souza, Adriana V. A.; Costa, Ingrid C. R.; Rezende, Michelle J. C.; da Silva, Joao F. Cajaiba; de Souza, Rodrigo O. M. A.
  Journal of Molecular Catalysis B: Enzymatic (2016), 123 (), 41-46CODEN: JMCEF8; ISSN:1381-1177. (Elsevier B.V.)
  Biodiesel is a mixt. of fatty acid alkyl esters with properties similar to petroleum-based diesel. Thus, biodiesel can be used as either a substitute for diesel fuel or, more commonly, in a fuel blend. Biodiesel prodn. can be catalyzed with mineral acids or bases or enzymes. The use of real-time techniques for monitoring the reaction and evaluating the efficiency of the catalyst can be of great use for optimizing the reaction and monitoring the process. In the present work, an in-line real-time methodol. was used to evaluate and compare the kinetics of a reaction catalyzed with homo (hydrochloric acid) and heterogeneous (the enzymes Novozym 435, Lipozyme RM, and Lipozyme TL) catalysts. The esterification of oleic acid with ethanol was used as the reaction model. The study used attenuated total reflexion/Fourier transform IR (ATR/FT-IR) and a single partial least squares (PLS) regression model to evaluate the kinetics of the various catalysts, without multiple calibrations, with validation by GC-MS. Novozym 435, which showed complete conversion after 165 min, was the best catalyst for this reaction. Lipozyme RM and Lipozyme TL had inferior conversion after the same amt. of time, in agreement with the literature. All enzymic catalysts showed higher conversion than hydrochloric acid at the same reaction conditions.
37. 37
  Rueping, M.; Bootwicha, T.; Sugiono, E. Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis. Beilstein journal of organic chemistry 2012, 8 (1), 300– 307, DOI: 10.3762/bjoc.8.32
  37
  Continuous-flow catalytic asymmetric hydrogenations: reaction optimization using FTIR in-line analysis
  Rueping, Magnus; Bootwicha, Teerawut; Sugiono, Erli
  Beilstein Journal of Organic Chemistry (2012), 8 (), 300-307, No. 32CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  The asym. organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors has been developed. Reaction monitoring was achieved by using an in-line ReactIR flow cell, which allows fast and convenient optimization of reaction parameters. The redn. reactions proceeded well and the desired products were isolated in high yield and in excellent enantioselectivity. The synthesis of the target compds. was achieved using chiral cyclic phosphates I (R = 9-anthracenyl, 9-phenanthryl) as organocatalysts and Hantzsch dihydropyridines as hydrogen donors.
38. 38
  Brodmann, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V. Continuous preparation of arylmagnesium reagents in flow with inline IR monitoring. Org. Process Res. Dev. 2012, 16 (5), 1102– 1113, DOI: 10.1021/op200275d
  38
  Continuous Preparation of Arylmagnesium Reagents in Flow with In-line IR Monitoring
  Brodmann, Tobias; Koos, Peter; Metzger, Albrecht; Knochel, Paul; Ley, Steven V.
  Organic Process Research & Development (2012), 16 (5), 1102-1113CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  A newly developed microscale React-IR flow cell was used as a convenient and versatile in-line anal. tool for Grignard formation in continuous flow chem. processing. The LiCl-mediated halogen/Mg exchange reaction was used for the prepn. of functionalized arylmagnesium compds. from aryl iodides or bromides. Furthermore, in-line IR monitoring was used for the anal. of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.
39. 39
  Rodriguez-Zubiri, M.; Felpin, F.-X. Analytical Tools Integrated in Continuous-Flow Reactors: Which One for What?. Org. Process Res. Dev. 2022, 26 (6), 1766– 1793, DOI: 10.1021/acs.oprd.2c00102
  39
  Analytical Tools Integrated in Continuous-Flow Reactors: Which One for What
  Rodriguez-Zubiri, Mireia; Felpin, Francois-Xavier
  Organic Process Research & Development (2022), 26 (6), 1766-1793CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  A review. The concept and practices of chem. synthesis are being profoundly transformed toward the development of fully autonomous continuous processes. Crit. to the development of autonomous continuous processes is the efficient monitoring of the reaction compn. and product quality by in-line and online analyses. The in-line/online acquisition of anal. data allows one to monitor at regular intervals the reaction compn., including hazardous or air-sensitive intermediates with the possibility of adapting reaction parameters or interrupting the flow process when a chem. or tech. failure is detected. This review presents the main in-line/online anal. tools that can be integrated into flow reactors for the monitoring of chem. reactions. This contribution is more a guide at the service of synthetic chemists illustrated by selected published examples from leading research labs. than an exhaustive list of published articles. Ultimately, we would like this review to be an answer to the following recurrent, yet complex, question: "Which is/are the most suitable anal. soln.(s) to monitor my chem. reaction ".
40. 40
  Perkampus, H.-H. In UV-VIS Spectroscopy and Its Applications; Springer Science & Business Media, 2013.
  There is no corresponding record for this reference.
41. 41
  Chung, R.; Hein, J. E. Automated solubility and crystallization analysis of non-UV active compounds: integration of evaporative light scattering detection (ELSD) and robotic sampling. Reaction Chemistry & Engineering 2019, 4 (9), 1674– 1681, DOI: 10.1039/C9RE00057G
  There is no corresponding record for this reference.
42. 42
  Yossif, N. A.; Kandile, N. G.; Abdelaziz, M. A.; Negm, N. A. Preparation and characterization of polymeric dispersants based on vegetable oils for printing ink application. Prog. Org. Coat. 2017, 111, 354– 360, DOI: 10.1016/j.porgcoat.2017.06.005
  42
  Preparation and characterization of polymeric dispersants based on vegetable oils for printing ink application
  Yossif, Nadia A.; Kandile, Nadia G.; Abdelaziz, Mohamed A.; Negm, Nabel A.
  Progress in Organic Coatings (2017), 111 (), 354-360CODEN: POGCAT; ISSN:0300-9440. (Elsevier B.V.)
  In this work, a novel vegetable oil-based polymers were prepd. by epoxidn. of soybean oil (SBO) and castor oil (CO) followed by ring opening reaction of epoxidized oil with polyether amine and poly propylene glycol. The prepd. polymers were characterized by FTIR and GPC. The properties of vegetable oils and epoxidized vegetable oil (EVO) were studied. The prepd. polymers were employed as novel polymeric dispersants for pigment dispersion in solvent based printing ink application. The mech. and optical properties of prepd. ink were studied. The net tech. properties of the new ink formulations are relatively comparable to the prepd. printing ink from std. polymeric dispersant. The polymeric dispersant 2 (PD2) and polymeric dispersant 4 (PD4) gave the best optical and mech. properties among the prepd. polymers.
43. 43
  Pirouz, S.; Wang, Y.; Chong, J. M.; Duhamel, J. Chemical modification of polyisobutylene succinimide dispersants and characterization of their associative properties. J. Phys. Chem. B 2015, 119 (37), 12202– 12211, DOI: 10.1021/acs.jpcb.5b04515
  43
  Chemical Modification of Polyisobutylene Succinimide Dispersants and Characterization of Their Associative Properties
  Pirouz, Solmaz; Wang, Yulin; Chong, J. Michael; Duhamel, Jean
  Journal of Physical Chemistry B (2015), 119 (37), 12202-12211CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
  The secondary amines found in b-PIBSI dispersants prepd. by attaching two polyisobutylene chains to a polyamine core via two succinimide moieties were reacted with ethylene carbonate (EC). The reaction generated urethane bonds on the polyamine core to yield the modified b-PIBSI dispersants (Mb-PIBSI). Five dispersants were prepd. by reacting 2 molar equivalent (meq) of polyisobutylene terminated at one end with a succinic anhydride moiety (PIBSA) with 1 meq of hexamethylenediamine (HMDA), diethylenetriamine (DETA), triethylenetetramine (TETA), tetraethylenepentamine (TEPA), and pentaethylenehexamine (PEHA) to yield the corresponding b-PIBSI dispersants. Characterization of the level of secondary amine modification for the Mb-PIBSI dispersants with traditional techniques such as FTIR and 1H NMR spectroscopies was greatly complicated by interactions between the carbonyls of the succinimide groups and unreacted secondary amines of the Mb-PIBSI dispersants. Therefore, an alternative procedure was developed based on fluorescence quenching of the succinimides by secondary amines and urethane groups. The procedure took advantage of the fact that the succinimide fluorescence of the Mb-PIBSI dispersants was quenched much more efficiently by secondary amines than by the urethane groups that resulted from the EC modification of the amines. While EC modification did not proceed for b-PIBSI-DETA and b-PIBSI-TETA certainly due to steric hindrance, 60 and 70% of the secondary amines found in the longer polyamine core of b-PIBSI-TEPA and b-PIBSI-PEHA had reacted with EC as detd. by the fluorescence quenching anal. Furthermore, the ability of the Mb-PIBSI dispersants to adsorb at the surface of carbon black particles used as mimic of the carbonaceous particles typically found in engine oils was compared to that of their unmodified analogs.
44. 44
  Miyai, Y.; Formosa, A.; Armstrong, C.; Marquardt, B.; Rogers, L.; Roper, T. PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy. Org. Process Res. Dev. 2021, 25 (12), 2707– 2717, DOI: 10.1021/acs.oprd.1c00299
  44
  PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy
  Miyai, Yuma; Formosa, Anna; Armstrong, Cameron; Marquardt, Brian; Rogers, Luke; Roper, Thomas
  Organic Process Research & Development (2021), 25 (12), 2707-2717CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  The strategies and exptl. methods for implementation of process anal. technol. (PAT) on the mobile pharmaceutical manufg. system, Pharmacy on Demand (PoD), are discussed. With multiple processes to be monitored on the PoD end-to-end continuous manufg. process, PAT and its real-time process monitoring capability play a significant role in ensuring final product quality. Here, we discuss PAT implementation for real-time monitoring of an intermediate and API concns. with in-line Fourier-transformed IR and Raman spectroscopy for the five-step continuous synthesis of ciprofloxacin on the PoD synthesis unit. Two partial least squares regression models were built and verified with flow chem. expts. to obtain a root-mean-square error of prediction (RMSEP) of 2.2 mg/mL with a relative error of 2.8% for the step 2 FlowIR model and a RMSEP of 0.9 mg/mL with a relative error of 2.8% for the step 5 Raman model. These models were deployed during an 11 h step 1-3 and a 5 h step 4-5 continuous ciprofloxacin synthesis run performed on the PoD system. In these runs, the real-time prediction of intermediate and product concn. was achieved with an online model processing software (Solo_Predictor) and a PAT data collection and management software (synTQ).
45. 45
  Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Wittkamp, B.; Goode, J. G.; Gaunt, N. L. ReactIR flow cell: a new analytical tool for continuous flow chemical processing. Org. Process Res. Dev. 2010, 14 (2), 393– 404, DOI: 10.1021/op900305v
  45
  ReactIR Flow Cell: A new analytical tool for continuous flow chemical processing
  Carter, Catherine F.; Lange, Heiko; Ley, Steven V.; Baxendale, Ian R.; Wittkamp, Brian; Goode, Jon G.; Gaunt, Nigel L.
  Organic Process Research & Development (2010), 14 (2), 393-404CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  A newly developed ReactIR flow cell is reported as a convenient and versatile inline anal. tool for continuous flow chem. processing. The flow cell, operated with ATR technol., is attached directly into a reaction flow stream using std. OmniFit (HPLC) connections and can be used in combination with both meso- and microscale flow chem. equipment. The iC IR anal. software (version 4.0) enables the monitoring of reagent consumption and product formation, aiding the rapid optimization of procedures. Short-lived reactive intermediates can also be obsd. in situ, giving further mechanistic insight into complex transformations.
46. 46
  Ansys Fluent, Release 2021R2; Ansys, Inc., Canonsburg, Pennsylvania, U.S.A., 2021.
  There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.3c00299.
- The reproducibility of the experimentally measured IR signal response for the three most efficient configurations, the structured orthogonal mesh details used for the CFD simulations, supporting data for the IR signal response for different mixtures, supporting data for the steady-state velocity profile and transient behavior of the normalized IR signal using CFD, and plots of experimentally measured temperatures and flow rates versus time for two different cases (PDF)
- op3c00299_si_001.pdf (1.22 MB)
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Impact of Flow Configurations on Response Time and Data Quality in Real-Time, In-Line Fourier Transform Infrared (FTIR) Monitoring of Viscous FlowsClick to copy article linkArticle link copied!

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SPECIAL ISSUE

1. Introduction

2. Experimental Section

2.1. IR Instrument

Figure 1

2.2. Investigated Flow Path Configurations

Figure 2

2.3. Continuous Flow Setup

Figure 3

2.4. Experimental Flow Mixtures

2.5. Infrared (IR) Signal Analysis

Figure 4

2.6. Computational Fluid Dynamics (CFD)

3. Results and Discussion

3.1. Infrared (IR) Signal Response to Flow Changes Using Different Configurations

Figure 5

Figure 6

3.2. 2D Computational Fluid Dynamics (CFD) Simulations

Figure 7

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Figure 10

3.3. Effect of Fluid Viscosity on Infrared (IR) Signal Response Time

Figure 11

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3.4. Pressure Drop across the Flow Cell

Figure 13

4. Conclusion

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Impact of Flow Configurations on Response Time and Data Quality in Real-Time, In-Line Fourier Transform Infrared (FTIR) Monitoring of Viscous Flows
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