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Jun 6, 2017 - and Michael G. Organ*,†,‡. †. Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario M3J 1P3, Canada. ‡. ...
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A Multi-Configuration Valve for Uninterrupted Sampling from Heterogeneous Slurries – An Application to Flow Chemistry Jee S. Kwak, Wenyao Zhang, Daniel Tsoy, Howard N. Hunter, Debasis Mallik, and Michael G. Organ Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 06 Jun 2017 Downloaded from http://pubs.acs.org on June 7, 2017

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A Multi-Configuration Valve for Uninterrupted Sampling from Heterogeneous Slurries – An Application to Flow Chemistry Jee S. Kwak,1 Wenyao Zhang,1 Daniel Tsoy,1 Howard N. Hunter,1 Debasis Mallik,1 Michael G. Organ1,2,* 1

Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario,

Canada, M3J 1P3 2

Centre for Catalysis Research and Innovation (CCRI) and Department of Chemistry,

University of Ottawa, 10 Marie-Curie, Ottawa, Ontario, Canada, K1N 6N5

ABSTRACT:

Heterogeneous chemical reactions that produce precipitates are generally

considered to be poor choices for adaptation to a flowed format. Among various complexities associated with working with slurries, sampling from a moving slurry is perhaps the most challenging task as the flow-paths inside the sampling device quickly become clogged by the heterogeneous reaction matrices. We report here a new sampling strategy using a multi-configuration sampling valve that was found to be an effective alternative to conventional sampling methods. When a model reaction that produces crystalline solid byproducts was performed using a traditional two-configuration valve, the flow-paths inside the sampling valve quickly clogged and the process had to be shut

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down. Using the new multi-configuration sampling protocol, we could maintain clear flow-paths inside the valve for extended periods of operation. With this technology in hand, we could obtain reproducible data from sampling operations and build a sampling mechanism capable of monitoring flowed chemical reactions that contain particulates at the outset, or produce them over time.

Key Words: Flow chemistry, in-line sampling, in-line analysis

INTRODUCTION In recent years, there has been a growing trend in the pharmaceutical industry towards continuous manufacturing. Continuous operations have numerous advantages over traditional batch processes, including minimizing waste,1,2 as well as consuming less energy,3 and raw materials.4 One important example of such continuous operations is flow chemistry, where reactants are combined and flowed through a tube to make products on-demand.5,6 One important limitation for flow is that reaction mixtures consisting of slurries often end up clogging various parts inside the reactor including the components used to extract reaction output for analysis.7 Adapting even a simple chemical reaction from batch to flow format often requires careful selection of reaction conditions. Ideally, one could create a system to automate iterative process optimization, including transformations containing suspensions and slurries. However, the components responsible for sampling must remain functional at all times and, more importantly, under conditions prone to clogging.

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There have been several scientific advancements in the field of flow chemistry that focus on the issues relating to flowing solids; the CofloreTM Agitated Cell Reactor (ACR) can accommodate solid-forming reactions (e.g., oxidation of morpholine by iodine) in flow8 and Jensen and coworkers also reported a miniature Continuous StirredTank Reactor (CSTR) suitable for continuous flow reaction.9 Integration of an analytical sampling mechanism to these reactors could lead to a flow platform complete with Process Analytical Technology (PAT) capabilities. A PAT-enabled reactor can be used to optimize and monitor flow chemical processes on a continuous basis rather than by postreaction analysis. Since 2005, we have been working on the development of flow reactor technology10,11,12 with recent efforts focused on automation and reaction optimization.13,14 An Information-based Rapid and Intelligent Sampling (IRIS) protocol has been integrated into in-house software to test the capability of our integrated analytics toward building a completely automated flow reactor system. Solids offer special challenges to the implementation of such technology. By implementing a filtration device, we hope to ensure that the permeate (i.e., the filtrate) will be free from particulates before analysis and does not clog the flow-paths inside the sampling mechanism. Moreover, multiple filtration operations during one synthetic run requires the filter membrane to be brought back to its original state repetitively for subsequent sampling events. There are examples in the literature of how an inline filtration mechanism could be used to filter samples from uninterrupted heterogeneous flow. Garnaey and coworkers15 used Cross-Flow Filtration (CFF) where the heterogeneous fluid is moved tangentially on a filter bed and the permeate is continuously isolated from the retentate (i.e., the residue). In their setup,

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the filter bed is an integral part of the reactor fluidics and the process pressure is affected due to the build-up of particulates on the filter bed. The permeate flux, which is a measure of the rate at which the filtrate exits the filter membrane, could be concomitantly impacted. A similar strategy for a continuous CFF was described by Szita and coworkers where the efficiency of the filtration operation was also found to be dependent on the process flow-rate and the back-pressure, which is linked to the corresponding internal diameter of the flow tube.16 Although these strategies were demonstrated to be effective for certain chemical or biochemical transformations, the trans-membrane pressure, the key driving force, was found to be dependent on the process flow-rate, a critical parameter for chemical processes in flow. A successful filtration device that is capable of handling slurries must not affect any of the critical process parameters of the flowed reaction during operation. With that in mind, we envisioned that a frontal filtration mechanism (i.e., deadend filtration) could be equipped with an option to systematically clean the filter membrane to produce a viable inline, continuous filtration strategy. This would allow for control over the accumulation of particulates on the filter membrane and when equipped with a switchable valve technology, the filter membrane can be brought back to its original state by flushing the filter membrane with a clean fluid prior to the next sampling event. This strategy would prevent significant build-up of particulates on the filter membrane over time. RESULTS AND DISCUSSION Equipment Description for Two-Configuration Sampling Strategy:

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To achieve sampling from a slurry, while not affecting steady-state reaction conditions (e.g., pressure, temperature, flow-rate), we introduced a ten-port sampling valve to accomplish inline filtration. The sampling valve can assume more than one valve configuration. In one configuration, the valve is capable of filtering particulates from a heterogeneous stream and loading a desired amount of the filtrate in a sampling loop situated downstream of the filtration device, which is termed as a ‘load configuration’. In the other configuration, the filtrate in the sampling loop is in fluid communication with the analytical system. Also in this configuration, the filter membrane is in fluid communication with an external pump that can move clean fluid through the filter membrane in the opposite direction to remove particulates (the residue) from the membrane bed and bring the membrane back to its original state. During this time, the filtered fluid (i.e., the analyte) in the sampling loop is transported to the analytical device via a sample delivery pump, which is an ‘inject configuration’. For our setup, we used HPLC for analysis of the reactor output (the filtrate) and monitored the amounts of the chromatographed analytes using a photo-diode array detector. Our first objective was to use this two-configuration protocol to take a sample from a heterogeneous flow stream and examine the performance of the sampling valve. Figure 1 illustrates the peripheral connections of the different fluid paths around the ten-port sampling valve (V1). The sampling valve was connected to the flow-reactor (R) via port 1 and to a product collection assembly (PCA) via port 10. A pressure creation device (PCD), which was a part of the PCA, remained in fluid communication with reactor R via port 10 and helps retain liquids in reactor R during the flow reaction by applying a fixed amount of back-pressure on the liquids in the reactor.17 In all possible

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configurations of the sampling valve (V1), ports 1 and 10 remained in fluid communication, thus maintaining the process pressure inside the flow reactor throughout the sampling event. A set of three positive-displacement pumps (PR1/PR2/PR3) are in fluid communication with the flow-reactor (R) and can move output from the flow reactor to the sampling valve. A bi-directional inline filter (F) was connected through ports 2 and 5 and a sampling loop (LS) of 30 µL was mounted on sampling valve V1 between ports 6 and 9. Two positive-displacement pumps were also connected to the sampling valve. The first pump (shown in Figure 1 as PF) was responsible for pumping fresh solvents via port 4 and is responsible for restoring the inline filter to its original state. The second pump (shown in Figure 1 as PD), which was connected to the sampling valve via a second twoposition valve (V2), was responsible for transporting the analyte in sampling loop LS to an analytical platform (A). Valve V2 was equipped with a second loop (LI, 45 µL), which was used to insert additives as necessary for analysis (e.g., an internal standard). The internal standard solution was supplied to loop LI from an external pump (PI). During operation, valve V1 receives the heterogeneous fluid through port 1 and, depending on its configuration, the valve diverted the fluid either directly to the PCA (via port 10) or to the inline filter (via port 2).

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Figure 1. Schematic representation of the ‘load’ (left) and ‘inject’ (right) configurations for the ten-port, two-configuration sampling valve (V1). Movable slits on the rotor are numbered as S1, S2, S3, S4, and S5. Legend: PR1/R2/R3 = Reagent pumps; R = Flow reactor; V1 = Sampling valve; PCD = Pressure Creating Device; PCA = Product Collection Assembly; A = Analytics; F = Inline filter; LS = Sampling loop; PF = Filter pump; PD = Sample Delivery Pump; V2 = Internal Standard valve; LI = Loop for the internal standard solution; PI=Pump for the internal standard solution; W = waste. Direction of flow were indicated in blue (from PR1/R2/R3), in orange (from PF), in green (from PD), and in black (from PI). The numbers in black denote ports.

Description of Sampling Operation Using the Two-Configuration Valve: As discussed above, the sampling valve (V1) can adopt two configurations; ‘load’ and ‘inject’. In the load configuration, valve V1 establishes fluid communication between ports 1 and 2 and allowed the reactor output to flow towards sampling loop LS via inline filter F. Specifically, when sampling valve V1 is set at a load configuration, five slits (S1, S2, S3, S4, and S5; Figure 1), which are located on a movable seal (i.e., the rotor),

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establish fluid communication between ports 1 and 2, 3 and 4, 5 and 6, 7 and 8, and 9 and 10, respectively. In this configuration, the reactor output comes into contact with inline filter F via slit S1 and the filtrate enters sampling loop LS via slit S3. The PCA remains in contact with sampling loop LS via slit S5 during this time. Conversely, in the inject configuration, reactor R is in direct communication with the PCA via ports 1 and 10 and the reactor output does not flow into the inline filter or the sampling loop. In this configuration, slits S1, S2, S3, S4, and S5 establish fluid communications between ports 1 and 10, 2 and 3, 4 and 5, 6 and 7, and 8 and 9, respectively. In this configuration, slit S1 receives the reactor output through port 1 and channels the fluid directly into the PCA through port 10. During this time, slits S2 and S3 set pump PF in fluid communication with inline filter F. Pump PF pushes a fresh batch of solvent in the opposite direction through the inline filter to move the solid (the residue) upstream of the filter bed to waste (W), thus cleaning the filter. In this configuration, slits S4 and S5 are responsible for establishing fluid communications between pump PD and the analytics via sampling loop LS. Thus, the content of the fluid downstream of the filter membrane (the filtrate) is delivered to the analytical instrument (i.e., A in Figure 1). Sample delivery pump PD can also transport an internal standard solution from loop LI during this time.

Evaluation of the Two-Configuration Valve, Continuous Filtration Strategy: We decided to test this ‘load-inject’ two-configuration valve operation using the nucleophilic aromatic substitution reaction (SNAr) of 2-nitrofluorobenzene (1) with benzyl amine (2) to give N-(o-nitrophenyl)benzylamine (3) in the presence of a nonnucleophilic base (Hünig’s base) (Scheme 1).18 The reaction, which was performed at 0.1

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M in dimethyl acetamide (DMA) (flow-rate: 99 µL/min), was found to produce a thick slurry. In the past, this reaction was performed in flow and the reactor output was first isolated and then manually processed before performing any analytical measurements.9a The thick slurry obtained from the reactor must be diluted and then filtered in order to obtain a particulate-free analytical grade sample suitable for an HPLC injection. Using the current setup, we hoped to sample from this heterogeneous output without having to manually intervene during analysis.

Scheme 1. Flow SNAr reaction of 2-nitrofluorobenzene (1) with benzyl amine (2) using microwave heating. The formation of solid benzyl ammonium fluoride salt (4) occurs during this transformation. Three reagent pumps (PR1/R2/R3) moved three reagent solutions (0.3 M solutions of 1, 2, and Hünig's base in DMA) towards reactor R at the same flow-rate (33 µL/min each) to give a net solution of 0.1 M inside the reactor with respect to the starting materials. The reaction mixture was heated to various temperatures ranging between 25 °C and 100 °C. Sampling valve V1 was rotated from the inject configuration to the load configuration to isolate a portion of the reactor output in the sampling loop (LS). The valve was configured to stay at the load configuration for one minute, flowing 99 µL of the reactor output towards the sampling loop. Once the sampling loop was overfilled, the valve was switched back to the inject configuration and the filtrate was moved from the sampling loop (LS) to the HPLC instrument (i.e., A) with a known amount of a transport

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solvent (acetonitrile in this case) by pump PD using a similar protocol that we previously reported.12a Also during this time, pump PF moved a fresh batch of cleaning solvent (DMA in this case) through inline filter F, but in the opposite direction. Prior to the transport of analyte from loop LS to the analytics by pump PD, an internal standard solution (in this case, a 0.2 M solution of 2-methoxynaphthalene in acetonitrile) was added from valve V2. Pump PD moved both the internal standard solution and the analyte to a clean vial along with a known volume of the transport solvent, which also served as the diluent for analysis in this case. The analytical station was equipped with an agitator and the solution was shaken for 1 min. after which a sample was injected using a robotic device to the HPLC column. While no product was formed at room temperature, we saw product in the first sample taken after the reactor had been set to 100 °C (Figure 2). However, analytical results were not consistent in subsequent sampling events. Despite continuing to run the flow reaction at 100 °C no product was observed from the subsequent analytical runs, which we knew to be erroneous.

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Figure 2. Graphical representation of the results obtained using the two-configuration valve protocol. Striped, clear, and solid black boxes represent the amounts (in mM) of 2fluoronitrobenzene (1), 2-methoxynaphthalene (the internal standard (ISTD)), and N-(onitrophenyl)benzylamine (3) respectively. The upper x-axis indicates times at which sampling was performed during a single flow experiment. To investigate the source of the analytical failure, we first lowered the process temperature to see if thermal expansion of the internal components of the sampling valve (e.g., the seal) was responsible for the sampling failure. When the temperature of the reactor was brought back to 80 °C, at which temperature we previously observed some formation of the product, we failed to observe any peak from 2-fluoronitrobenzene (the reactant; 1) or N-(o-nitrophenyl)benzylamine (the product; 3). Failure to obtain any analyte from the sampling valve led us to propose that some portion of the fluid paths responsible for the sampling may have been blocked. Interestingly, the amount of the internal standard was found to be consistent throughout the experiment (RSD: 1.5 %).

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This was a strong indication of failure in the sampling valve itself. The flow-paths responsible for the transport of the internal standard solution (i.e., all connections from port 6 to port 9 of valve V1, reading counter-clockwise in Figure 1) must be clear in order for the observed amount of the internal standard to remain constant. We also noticed that during the malfunctioning of valve V1, pump PF did not experience any resistance from any blockage, as this would automatically cause the pump to switch off. At times, some of the reagent pumps (PR1/R2/R3) experienced occasional resistance from the fluid paths downstream. Physical inspection of the filter membrane did not show any signs of residual solids clinging to the filter. This confirmed that slits S2 and S3 were in good condition at the inject configuration. Consequently, we narrowed down our investigation to all connecting flow-paths between ports 2 to 10 (reading clockwise) of valve V1 for a possible constriction. Recognizing that the most sensitive portions of the flow-paths in our design were the slits on the rotor, we focused attention to the slits that are active between ports 2 to 10 (reading clockwise in Figure 1) in both configurations during sampling. This drew our attention to slit S1, which remained at the receiving end of the heterogeneous stream from the reactor at both configurations (load and inject). To further confirm our diagnosis, we continued to pump the reagents beyond the point when the sampling valve failed to extract any analyte (i.e., the process temperature was maintained at 100 °C) and confirmed the blockage at slit S1 when the reagent pumps ultimately stalled. As slit S1 became clogged, it was possible to observe the accumulation of the precipitates inside of the flow path in front of port 1 of the sampling valve as illustrated in Figure 3.

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Figure 3. Photograph of the white precipitate backing up in the flow line leading to the sampling valve V1 and slit S1. The slit in question either had to be manually cleaned or the fluid entering the slit needed to be sufficiently diluted to ensure that the accumulation of particulates inside the slit did not occur in the first place. Given that our objective was to build a sampling device that can routinely handle relatively thick heterogeneous mixtures, we needed to find an easily implementable, yet universal solution that does not require any manual intervention during operation of the flow and sampling devices. One such solution would be to adopt a multi-configuration sampling protocol by taking advantage of all ten available inject and load configurations of the sampling valve (V1). Equipment Description for Multi-Configuration Sampling Strategy: In the two-configuration protocol, the sampling valve was rotated only by an angle of 36°, first clockwise and then counter-clockwise (or vice versa). The multiconfiguration valve can be rotated by an integral multiple of 36° (i.e., 72°, 108°, 144°, 180°, 216°, 252°, 288°, and 324°) and still achieve load and inject configurations. Importantly, the slits responsible for establishing fluid communications between individual peripheral components (e.g., the reactor, the filter, the PCA, the sampling loop,

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the analytics, pump PF and PD) can be varied. This multi-configuration strategy would allow us to use all five slits instead of using one specific slit (e.g., S1 in the twoconfiguration example) for receiving the heterogeneous fluid from the reactor. The slit that was set to receive the heterogeneous fluid in one specific configuration can be moved to a new location in the next inject configuration so the flow-path of the slit can be thoroughly cleaned. The multi-configuration valve (V1a) is similar to the two-configuration valve (V1) in that it has the same number of ports and connectivity to peripheral devices (Figure 4). The rotor of the multi-configuration valve has the ability to rotate the seal by 360°, allowing it to toggle between any two configurations. The ten-port multiconfiguration valve (V1a) possessed ten distinct configurations, five of which were the load configurations (C2, C4, C6, C8, and C10) and the other five were the inject configurations (C1, C3, C5, C7, and C9). Description of Sampling Operation Using the Multi-Configuration Valve: In configuration C1, reactor R is in direct fluid communication with the PCD via slit S1. When the rotor is moved clockwise by 36° or anti-clockwise by 324°, valve V1a adopts configuration C2, which is one of the five available load configurations. In this configuration, reactor R is in fluid communication with the PCD via the inline filter and the sampling loop. When the rotor of the sampling valve is rotated by another 36° clockwise or 324° anti-clockwise from configuration C2, the valve adopts another inject configuration (C3 in Figure 4). Both C1 and C3 configurations are functionally same (degenerate) except the slits connecting reactor R and the PCD (S1 in C1 versus S2 in C3) are different. Similarly, the rotor can be further moved clockwise by 36° at a time to

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achieve C4 to C10 configurations. All inject configurations C1, C3, C5, C7, and C9 are functionally degenerate except the slits connecting the reactor to the PCD are S1, S2, S3, S4, and S5, respectively. Similarly, all load configurations also use different slits for fluid communications, but deliver same load functions. Any of the five slits on the rotor (S1, S2, S3, S4, and S5) may be placed between ports 3 and 4

Figure 4. Schematic representation of all ten-available load (C2, C4, C6, C8, C10) and inject (C1, C3, C5, C7, C9) configurations of the multi-configuration sampling valve

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(V1a). During sampling, the rotor of valve V1a is moved following a specific sequence of configurations, not necessarily in the order shown in the figure above. In this figure, the rotor was rotated clock-wise by 36° at a time to achieve all ten configurations. Legend: V1a = multi-configuration sampling valve; PCD = Pressure creating device; PCA = Product collection assembly; F = Inline filter, PF = Filter pump; PD = Sample delivery pump; LS = Sampling loop; V2 = Internal standard valve; A = Analytics; W = Waste.

during a load configuration or between ports 2 and 3 during an inject configuration for cleaning. Pump PF moves clean solvent (e.g., DMA) through the slit when an individual slit is placed between the above-mentioned ports. With the multi-configuration sampling valve (V1a) in hand, we developed a sequence of valve rotations where the specific slit that was exposed to the heterogeneous fluid from the flow reactor could be systematically cleaned before the same slit again received effluent from the reactor. It is important to note that in all configurations of multi-configuration valve V1a, reactor R remained in fluid communication with the PCA through ports 1 and 10, either directly (an inject configuration) or via the sampling loop (a load configuration). The sampling valve was initially set at configuration C1, which is an inject configuration. In this configuration, slit S1 received the heterogeneous fluid from the reactor. To extract a sample from the reactor, the rotor was next moved anti-clockwise by 108° (or clockwise by 252°) so that the valve can adopt configuration C8, which is a load configuration. In configuration C8, slit S5 was at the receiving end for the reactor output and slit S1 was placed between ports 3 and 4 and brought to fluid communication with pump PF. The rotor was then moved to an inject configuration (C7) so that a clean slit (S4) was set in contact with the reactor output and slit S5 was moved to a cleaning position (in this case,

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between ports 2 and 3). From C7, valve V1a was switched to the C4 configuration. In this configuration, slit S4 was cleaned and slit S3 during this time received the heterogeneous fluid from the reactor. The sequence continued further in the order of C3, C10, C9, C6, C5, C2, and back to C1.

Evaluation of the Multi-Configuration Valve, Continuous Filtration Strategy: Implementation of this multi-configuration-valve protocol in the SNAr reaction made a marked improvement in sampling results (see Figure 5). The constriction that previously caused the reagent pumps (PR1/R2/R3) to stall and the sampling operation to fail did not develop. The analysis of all samples was conducted after a set of samples were collected by rotating the valve systematically between a load and an inject configurations. The results (Figure 5) were consistent.

Figure 5. Graphical representation of the results obtained from the multi-configuration

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valve sampling protocol. Using the reaction illustrated in Scheme 1, a 1:1:1 molar ratio of 1:2:Hunig’s base was used. The striped, clear, and solid black boxes represent the amounts (in mM) of 2-fluoronitrobenzene (1), 2-methoxynaphthalene (the internal standard

(ISTD)),

and

N-(o-nitrophenyl)benzylamine

(3)

respectively.

Percent

conversions to the product (3) at a specific process temperature were shown beside the respective bar plots. The upper x-axis indicates times at which samples were collected from a single flow experiment. The timing of sampling was at 10 minute intervals except following a temperature change to ensure that steady state conditions were reestablished. As expected, the reported amounts for the internal standard showed a low RSD (2 %). In addition, the reactant and the product were found to be present in all samples, suggesting that sampling valve V1a successfully extracted the representative reactor outputs during each and every sampling. The model reaction (Scheme 1) was not expected to generate product at room temperature (~25 °C), but at 80 °C and above, a small amount of the product was detected from the sampling experiments. Typically, the solid by-product formed during the reaction would cause the flow-paths to clog under the two-configuration sampling protocol.19 As illustrated in Figure 5, this is not the case when the multi-configuration sampling method is applied. With this sampling method in hand, we set out to push the sampling valve using new reaction conditions that would improve conversion, thereby producing more solid byproduct and in so doing further stress valve V1a. In the new reaction condition, the concentrations of benzylamine (2) and Hünig’s base were doubled while the concentration of the 2-fluoronitrobenzene (1) was unchanged. The flow-rates of all three reagent pumps were kept the same (33 µL/min each). Figure 6 illustrates the

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concentrations of reactant 1, product 3, and the internal standard, both at room temperature where no product forms, and at 110 °C where a significant amount of the product forms (>60 % conversion to 3). The improved conversion led to considerably more solid byproduct in the lines leading from the reactor to the ten-port sampling valve, yet repetitive, consecutive sampling proceeded without any failure at the reagent pumps. Collection of the material upstream of the inline filter and analysis of the solid byproduct revealed that the white solid is the ammonium salt of 2 (i.e., 4) that forms during the reaction (for details see SI).

Figure 6. Graphical representation of the results obtained from the multi-configuration valve sampling. Using the reaction illustrated in Scheme 1, a 1:2:2 ratio of 1:2:Hunig’s base was used. The striped, clear, and solid black boxes represent the amounts (in mM) of 2-fluoronitrobenzene (1), 2-methoxynaphthalene (the internal standard (ISTD)), and N-(o-nitrophenyl)benzylamine (3) respectively. Percent conversions to the product (3) at

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a specific process temperature were shown beside the respective bar plots. The upper xaxis indicates times at which samples were taken from a single flow experiment. Encouraged by these early results, we set out to test the limits of the multi configuration valve using by pumping suspensions of particulates of known size distributions (e.g., silica gel (40 - 63 micron) and charcoal (44 - 149 micron)) through it for extended periods of time to see if valve failure resulted. In all cases, a 25 mg/mL slurry of particulates in acetonitrile was flowed at 50 μL/min flow-rate and the multiconfiguration valve was found to function without any interruption for the 8h. The suspensions were maintained by putting a small stir bar inside of a 20 mL syringe placed in a horizontal position on a stir plate; constant agitation by the stir bar kept the solids from settling out in the syringe and kept a steady suspension of particulates infusing into the valve (see SI for details). Samples of effluent from ports 3 and 7 from the silica gel experiment were placed under a microscope to inspect if the filtrate is free of particulates (Figure 7). The filtrate was found to be particulate-free as shown in Figure 7. This combined analysis demonstrates that the inline filter effectively removes all solids and the washing protocol thoroughly cleanse all ports and slits. When the same slurry was flowed using the conventional two-configuration valve protocol, clogging and system failure occurred within 5 minutes. Of note, the micrograph in panel B shows evidence of silica milling by the stir bar, causing the formation of fines that are not present in panel A. The presence of small particles might be anticipated to cause frit clogging, however this was not observed.

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Figure 7: Microscope photographs of: A) the silica gel slurry prior to being loaded into the syringe and pumped through valve V1a, B) the effluent from port 3, and C) the effluent from port 7 of valve V1a. In summary, the multi-configuration strategy for the sampling valve allowed us to monitor a model chemical process that was previously demonstrated to be a poor choice for flow format. At present, research is underway to integrate this multi-configuration sampling valve as a core analytical platform for automation of flow chemistry applications. A modified version of this protocol is currently under investigation for handling heterogeneous fluid streams in several other applications.

Supporting information including a detailed description of the equipment set up referred to in this manuscript has been included. This material is available free of charge via the Internet at http://pubs.acs.org

ACKNOWLEDGEMENT This work was supported by NSERC Canada in the form of a CRD grant and by the Eli Lilly Research Award Program (LRAP).

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S.; Organ, M. G. Angew. Chem. Int. Ed. 2006, 45, 2761. (c) Bremner, S.; Organ, M. G. J. Comb. Chem. 2007, 9, 14. (d) Shore, G.; Morin, S.; Mallik, D.; Organ, M. G. Chem. Eur. J. 2008, 14, 1351. (e) Shore, G.; Organ, M. G. Chem. Eur. J. 2008, 14, 9641. (f) Organ, M. G.; Shore, G.; Tsimerman, M. Beilstein J. Org. Chem. 2009, 5, No. 35. (g) Shore, G.; Yoo, W. J.; Li, C. J.; Organ, M. G. Chem. Eur. J. 2010, 16, 126. 11

(a) Ullah, F.; Samarakoon, T.; Rolfe, A.; Kurtz, R. D.; Hanson, P. R.; Organ, M. G.

Chem. Eur. J. 2010, 16, 10959. (b) Zang, Q.; Javed, S.; Ullah, F. Zhou, A.; Knudtson, C.

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A.; Bi, D.; Basha, F. Z.; Organ, M. G.; Hanson, P. Synthesis, 2011, 2743. (c) Hanson, P. R.; Organ, M. G.; Rolfe, A.; Samarakoon, T. B.; Ullah, F. J. Flow Chem. 2011, 1, 32. (d) Rolfe, A.; Ullah, F.; Samarakoon, T. B.; Kurtz, R. D.; Porubsky, P.; Neuenswander, B.; Lushington, G. H.; Santini, C.; Organ, M. G.; Hanson, P. R. ACS Comb. Sci., 2011, 13, 653. (e) Zang, Q.; Javed, S.; Porubsky, P.; Ullah, F.; Neuenswander, B.; Lushington, G. H.; Basha, F. Z.; Organ, M. G.; Hanson, P. R. ACS Combi. Sci. 2012, 14, 211. (f) Ullah, F.; Zang, Q.; Javed, S.; Porubsky, P.; Neuenswander, B.; Lushington, G. H.; Bash, F. Z.; Hanson, P. R.; Organ, M. G. Synthesis 2012, 44, 2547. (g) Zang, Q.; Javed, S.; Hill, D.; Ullah, F.; Bi, D.; Porubsky, P.; Neuenswander, B.; Lushington, G. H.; Santini, C.; Organ, M. G.; Hanson, P. R. ACS Combi. Sci. 2012, 14, 456. (h) Ullah, F.; Zang, Q.; Javed, S.; Zhou, A.; Knudtson, C. A.; Bi, D.; Hanson, P. R.; Organ, M. G. J. Flow. Chem. 2012, 2, 118. (i) Faisal, S.; Ullah, F.; Maity, P. K.; Rolfe, A.; Samarakoon, T. B.; Porubsky, P.; Neuenswander, B.; Lushington, G. H.; Basha, F. Z.; Organ, M. G.; Hanson, P. R. ACS Comb. Sci. 2012, 14, 268. 12

For the implementation of high-energy intermediates in flow, see: (a) Painter, T.

O.;Thornton, P. D.; Orestano, M.; Santini, C.; Organ, M. G.; Aubé, Chem. Eur. J. 2011, 17, 9595. (b) Nalivela, K. S.; Tilley, M.; McGuire, M. A.; Organ, M. G. Chem. Eur. J. 2014, 20, 6603. (c) Teci, M.; Tilley, M.; McGuire, M. A.; Organ, M. G. Chem. Eur. J. 2016, 22. 17405; (d) Teci, M.; Tilley, M.; McGuire, M. A.; Organ, M. G. Org. Proc. Res. Dev. 2016, 20, 1967. 13

(a) Somerville, K.; Tilley, M.; Li, G.; Mallik, D.; Organ, M. G. Org. Process Res. Dev.

2014, 18, 1315. (b) Tilley, M.; Li, G.; Savel, P.; Mallik, D.; Organ, M. G. Org. Process Res. Dev. 2016, 20, 517.

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Day, C.; Saledega, A.; Tilley, M.; Hunter, H. N.; Organ, M. G.; Wilson, D. J. Org.

Proc. Res. Dev. 2016, 20, 1738. 15

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The solid by-product, which was found to be benzyl ammonium fluoride (4), was

characterized by NMR spectroscopy and MS spectrometry. The spectra can be found in the supporting information.

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