Dispersion in Compartmentalized Flow Systems: Influence of Flow

Article pubs.acs.org/OPRD

Dispersion in Compartmentalized Flow Systems: Influence of Flow Patterns on Reactivity Neil Hawbaker,† Eric Wittgrove,† Bianca Christensen,† Neal Sach,‡ and Donna G. Blackmond*,† †

Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States

‡

S Supporting Information *

ABSTRACT: Rapid reaction screening in flow systems may help to reduce the time and material required to optimize, scale-up, and implement a flow process. Compartmentalization using small fluorous plugs has been implemented in several commercial reactors as a means for running a large number of isolated reactions in series within a flow reactor. Dye tracking, visual mixing, and reactivity studies are used to better understand the factors controlling dispersion within a commercial reactor. The role of dispersion on reactivity is elucidated using model reactions, and an optimized method for performing high-throughput screening is proposed.

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INTRODUCTION In the preceding two decades, there has been a developing interest in the use of continuous flow technology for the synthesis of small molecules.1 Comparisons between flow technology and traditional batch processes have been extensively discussed within the academic community.2 From a pharmaceutical perspective, several features of flow technology appear attractive for the synthesis of organic molecules, which may include simplifying scale-up, increasing safety, or accessing higher temperature and pressure regimes.3 Indeed, pharmaceutical laboratories have demonstrated the use of flow technology in controlling highly exothermic reactions4 and the safe handling of unstable intermediates.5 However, operation in flow reactors has often been limited by the need for homogeneous and fast reaction conditions, and in fact, the true potential of flow processes in the pharmaceutical industry remains to be delineated. Despite this, it is clear that flow processes are now being considered by the medicinal and process chemistry community as an additional tool for accomplishing transformations that prove difficult in standard batch reactors. In the ideal case, tubular flow reactors display what is known as “plug flow” behavior, where mixing and diffusion do not occur in the direction of the flow path (the axial direction).6 Each position within the reactor can be described as a “plug” with a given length (dx) and volume (dV) (Figure 1a). At steady state, each plug remains discrete and no mixing or diffusion occurs with the fluid before or after it. Thus, each plug can be envisioned as a small, well-mixed batch reactor in which the composition remains uniform and independent of the plugs adjacent to it. In ideal plug flow reactors, the distance traveled in the reactor dictates the reaction time. At steady state, all materials exiting a plug flow reactor have experienced identical reaction times. The narrow residence time distribution possible in the ideal case is one reason for the prevalence of plug flow reactors at both the industrial and laboratory scale. © XXXX American Chemical Society

Figure 1. Representation of (a) a plug flow reactor, (b) a uniform segmented flow reactor, (c) a segmented flow reactor used for reaction screening, and (d) a compartmentalized flow reactor.

Segmented flow is a type of biphasic flow pattern defined by alternating “segments” of immiscible liquids or gases.7 Often in segmented flow reactors, one phase is the reactant phase and the other phase is either an inert gas or liquid. Much like “plugs” within ideal plug flow reactors, no mixing or dispersion between a segment and the preceding and following segments is expected. However, while a plug flow reactor contains an infinite number of plugs, all with infinitesimally small volume, a segmented flow reactor contains a discrete number of Special Issue: Continuous Processing, Microreactors and Flow Chemistry Received: November 18, 2014

A

DOI: 10.1021/op500360w Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Organic Process Research & Development

Figure 2. (a) Schematic of an automated compartmentalized flow reactor. (b) A Conjure flow reactor.

While dispersion patterns within plug flow reactors and uniform segmented flow reactors have been previously characterized,9 the influence of dispersion on compartmentalized flow reactors has yet to be investigated in detail. This study is intended not as a quantitative analysis of dispersion within compartmentalized flow but rather as a general guide on the basic tenets of segmented flow aimed at the everyday user. The aim of this publication is to help the academic and industrial chemist understand how flow rate, solvent choice, segment length, and tubing material can influence the dispersion and thus influence the reactivity. While this investigation focuses specifically on the Conjure reactor system by Accendo, the principles of this study may also be extended to other popular automated flow systems, such as the AFRICA and ASIA systems by Syrris. Providing a simple working understanding of the interplay between reactivity and flow patterns may allow for increased yields, less reactor clogging, and broader reaction scope. In turn, this may make compartmentalized flow screening techniques more accessible to medicinal and process chemists.

segments, each with a fixed volume and length. Each segment is a well-mixed packet, and the distance traveled by the segment determines its residence time. Segmented flow systems provide a unique opportunity for reaction screening in flow (Figure 1c). High-throughput screening is a difficult task using traditional plug flow reactors because changing the reaction conditions within a traditional reactor requires flushing out the prior reaction contents, changing the reagent solutions, and returning the system to steady state. This process can be materialintensive and time-consuming. While segmented flow is one method for high-throughout screening, segmented flow reactors have been utilized for a variety of other purposes, and reviews of the current applications are reported elsewhere.7b−d Compartmentalized flow is a variation of segmented flow operation that is meant to address problems of nonideal cases where mixing between the reaction and carrier slugs may occur. In compartmentalized flow, each reaction segment is bracketed by a small volume of an immiscible solvent, typically a fluorous compound (Figure 1d). In concept, poor solubility of organic substrates in the fluorous solvent will prevent mass transport through the fluorous phase, providing a barrier to diffusion. The goal of this approach is to use fluorous spacers to isolate each reaction segment from the surrounding carrier solvent used to move the reaction segment through the reactor. Recently, the pharmaceutical industry has developed an interest in utilizing compartmentalized flow as a screening method in medicinal and process chemistry laboratories. In conjunction with major pharmaceutical companies, the Accendo Corporation has developed several reaction screening and library development platforms based on segmented flow technology (Figure 2). Nearly a dozen publications have been written on chemistry using Accendo reactors, including papers by industrial researchers at Abbott and Pfizer.8 To date, the scope of the chemistry studied using these reactors has been limited to rapid reactions, such as click cycloadditions and fast cyclizations. Moreover, the impact of changes in operational parameters such as carrier solvent, flow rate, and segment volume on the reactivity in these reactors has not yet been welldocumented. The purpose of this study is to probe how these factors influence the reactivity and to provide operational guidelines for medicinal and process chemists using such systems.

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RESULTS AND DISCUSSION

Characterization of Dispersion Patterns in Hastelloy Reactors. The Conjure automated flow platform (Figure 2) was used in these studies. This flow system prepares a reaction mixture, injects it into a coiled reactor, and collects the reaction mixture after a given residence time. The reactor is Hastelloy tubing with a diameter of 0.76 mm. In further studies, we compared this system to reactors of fluorinated polymer tubing with a diameter of 0.76 mm. The reaction mixture is formed through mixing of up to four reagents, which are selected from a carousel containing up to 52 stock solutions. The reaction mixture is bracketed on both sides by a small volume of fluorous solvent (spacer), forming the reaction segment. After injection, a flowing stream of a carrier solvent is used to move the reaction segment and its fluorous plugs through the reactor and then to a fraction collector. UV−vis spectroscopy was used to monitor the dispersion and mass transport patterns of the reaction segment. The reaction segment and the carrier solvent were doped with rose bengal (RB) and p-nitrophenol (PNP), respectively, as dyes. Segments were passed through the reactor at a fixed flow rate B


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Figure 3. (a) Example chromatogram of the ideal results for zero dispersion. The absorbances at 567 and 320 nm are correlated with the concentrations of rose bengal (RB) and p-nitrophenol (PNP), respectively. (b) Observed chromatogram 54 s postinjection at 0.70 mL/min.

and analyzed using a diode array detector as they passed through the exit. The mass transport in and out of the reaction segment was determined by monitoring the characteristic wavelengths of each dye. The fluorous spacers exhibit no absorbance at either dye’s characteristic wavelength, and hence, lack of absorbance indicates the presence of a fluorous spacer. In an initial experiment, a 200 μL reaction segment bracketed by spacers was injected into carrier solvent in the Hastelloy reactor and analyzed 54 s postinjection downstream. Ideally, if the contents of the reaction segment remain isolated, the RB dye will remain inside the reaction segment and PNP will be detected only in the running solvent, as shown in Figure 3a. However, UV monitoring indicated that mass transfer between the reaction segment and the surrounding carrier solvent occurs (Figure 3b). Even at this short residence time, PNP originally doped in the carrier solvent was found within the reaction segment. RB, the segment dopant, was detected in the carrier solvent behind the rear plug of fluorous solvent. This dispersion pattern was highly reproducible10 and showed that the contents of the reaction mixture do not remain isolated from the carrier solvent as originally anticipated. In order to develop a more dynamic picture of the mass transport, the segment composition was determined at several time points postinjection using the UV method by changing the position of the detector along the reactor system (Figure 4). This time-course analysis of the changes in segment composition indicated increased dispersion over time. Figures 3 and 4 show that as the segment progressed through the reactor, three major trends were observed:

Figure 4. Observed dye concentration as a function of reaction time at 1.00 mL/min (*1.54 mL/min for the case of 1.77 min residence time).

(b) The concentration of RB inside the reaction segment decreased. (c) A growing concentration of RB was seen in the carrier solvent behind the rear fluorous segment. These trends suggest a front-to-back dispersion pattern, where the carrier solvent enters the reaction segment through the front fluorous spacer and the reaction medium enters the trailing carrier solvent through the rear fluorous spacer. This is supported by the observation that the concentration of PNP was highest at the leading edge of the reaction segment. The same general trend was observed at all flow rates tested (0.48− 1.70 mL/min), but increased dispersion was seen at higher flow rates.10

(a) The concentration of PNP inside the reaction segment increased. C


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Figure 5. (a) Visualization of the mass transport process through the thin film and (b) anticipated UV output for dye tracking of the hypothetical segment in shown at the bottom of (a).

flow systems, such as continuous flow analyzers and toluene− water segments.9 From an adapted form of the model by Adler, the extent of dispersion, Xdisp, may be calculated in terms of a “Q factor”, Qdisp, according to eqs 1 and 2:

The mass transport around the bracketing fluorous phase can be rationalized by accounting for the wetting preference of each phase. In liquid−liquid multiphase flow, one liquid phase (the continuous phase) wets the walls of the reactor, whereas the other phase (the dispersed phase) is encapsulated within the wetting phase. Previous models of segmented flow suggest that the continuous phase is deposited as a thin film along the reactor walls as it travels through the reactor.9 This thin film may act as a conduit for mass transfer into any solvent or segments following the leading phase. UV analysis of the segment and solvent dyes suggested that the perfluorodecalin used as the spacer acts the dispersed phase within a continuous methanol phase. In these experiments, a thin film of methanol containing RB from the reaction segment forms along the reactor wall, mixing with the adjacent carrier solvent via radial diffusion (Figure 5a). Similarly, a thin film of the carrier solvent methanol containing PNP is formed along the reactor wall, where it mixes with the contents of the reaction segment. As the segment travels through the reactor, the solvent in the reactor segment (measured by [PNP]in segment) increases and the reactant concentration (measured by [RB]in segment) decreases. If convective mixing within the segment is rapid compared with diffusion (large Peclet number), the contents of the segment are rapidly mixed, resulting in uniform segment concentrations of PNP and RB, albeit at a lower than expected reactant concentration ([RB]in segment). A visualization of this process is provided in Figure 5a, with the anticipated UV output given in Figure 5b. The thin film model has been previously employed to characterize and predict dispersion within uniform segmented

∞

Xdisp =

Q disp =

∑k = 1

k exp(−Q disp)·Q disp ·C·Vs

k!

C·Vs

(1)

Vf d L = 4· f · Vs d t Ls

(2)

where C is the initial concentration of dye in the segment, Vs is the total segment volume, Vf is the volume of the thin film after the segment has traveled a length L, Ls is the length of the segment, df is the thickness of the thin film, and dt is the diameter of the tubing (Figure 6b). The Q factor is a volumedispersed term that gives the fraction of the volume of the main segment that has been dispersed via the thin film. Thus, the extent of dispersion can be determined from known variables (C, dt, Ls, and L) and the film thickness df, which is frequently estimated using Bretherton’s correlation (eq 3), df = 0.66d tCa 2/3

(3)

in which the capillary number, Ca, is given by eq 4, uμ Ca = σ

(4)

where μ is the viscosity of the continuous phase (in kg/ms), σ is the interfacial tension (in N/m), and u is the flow velocity (in m/s). While we were were unable to determine the interfacial D


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tension between methanol and perfluorodecalin experimentally, this value may be approximated from our time-course data and the fraction of dispersion. Xdisp was calculated for σ values ranging from 1−50 dyn/cm at three lengths L correlating to the distances traveled after 0.26, 0.71, and 1.27 min at 1.0 mL/min. These values were compared with the experimental dispersion Xdisp,expt, which was obtained from the integrated areas of dye found inside the segment (As) and outside the segment (Af) according to eq 5:

Xdisp,expt =

Af As + A f

(5)

As shown in Figure 6c, our experimental results are in good agreement with a model value of σ between 2 and 5 dyn/cm. With σ = 2.5 dyn/cm and the values given in Figure 6a, a predicted film thickness of 15.1 μm is anticipated at a flow rate of 1.0 mL/min. The model suggests that 90% dispersion of the segment will occur in under 6 min at the given flow rate. Thus, Figure 6d shows that a σ value of 2.5 dyn/cm can be used for an accurate prediction of the concentration gradient of the dispersed dye in this system. While an experimental verification of the interfacial tension would be required for quantitative validation, the model provides insight into methods for decreasing dispersion within the system. Namely, the model predicts that dispersion of these fluids in this Hastelloy compartmentalized flow system will be minimized by the following: (a) decreasing volumetric flow rate (b) increasing tube diameter (dt) (c) increasing interfacial tension (σ) (d) decreasing continuous phase viscosity (μ). (e) increasing segment volume (Vs) It is often suggested that dispersion and diffusion effects within a flow reactor can be mitigated by taking a “heart cut” from the center of the reaction segment, intended to be an area of the segment that remains uninfluenced by diffusion or dispersion (Figure 7a). However, our data from both predictive models (Figure 7b) and experiments12 show that at least 15% of the starting reaction concentration is lost even at low flow rates and short residence times and that higher losses are observed at higher flow rates, in keeping with the model insights noted above. Dispersion of the center cut of the

Figure 6. (a) Physical data for methanol and perfluorodecalin. (b) Visualization of L, df, and Vf. (c) Theoretical values of Xdisp (blue) for different values of interfacial surface tension σ and different residence times at 1.0 mL/min and dt = 0.762 mm, compared with the experimental Xdisp value (green) at each residence time. (d) Comparison of predicted and observed concentration gradients at σ = 2.5 dyn/cm.

Figure 7. (a) Experimental data of a “heart cut” in a 200 μL reaction segment (flow rate = 1.0 mL/min, tres = 1.27 min, dt = 0.762 mm). (b) Ideal concentration (green) compared with those predicted by the dispersion model (blue) for the “heart cut” at flow rates corresponding to tres = 1.0, 5.0, and 10.0 min ([dye]0 = 0.40 mM, Vs = 200 μL, σ = 2.5 dyn/cm, methanol/perfluorodecalin system in stainless steel). E


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Organic Process Research & Development segment is very pronounced at flow rates higher than 1.0 mL/ min and at residence times greater than 5 min. Characterization of Dispersion Patterns in Fluorinated Polymer Tubing. Previous studies of uniform water− toluene systems have shown that inversion of the dispersed and continuous phases can lead to changes in the dispersion and diffusion patterns.9a Such an inversion can be effected by changing the reactor wall material; we found that when PFA tubing is used, the wetting preferences of methanol and perfluorodecalin are inverted, with perfluorodecalin wetting the walls and acting as the continuous phase to encapsulate methanol, the dispersed phase. We investigated how this inversion in continuous phase would influence the observed flow patterns. PFA tubing is transparent, allowing for direct visual observation of the segment composition. In these studies, the reaction segment was doped with ergioglaucine blue (EB), and the carrier solvent was doped with RB. Each segment was bracketed with 100 μL of fluorous solvent and pushed through the reactor using the RB-doped methanol carrier solvent. Reaction segments were injected and recorded using a handheld camera as the segments progressed through the reactor (Figure 8a).

(c) The length of the front fluorous phase decreased, but at a lower rate than the rear fluorous phase. The disappearance of the fluorous phase and subsequent mixing of the carrier solvent and reaction segment suggest agreement with the proposed model. However, quantitative studies on the rate of fluorous phase disappearance were difficult for two reasons. First, a large volume of fluorous phase is lost in the tubing during segment preparation. During this process, observation of the segment is not possible, and the flow rates for sample preparation and injection are high and cannot be directly controlled. More importantly, direct measurement of fluorous phase disappearance is not possible because of nonuniform flow patterns within the reactor. As the fluorous phase travels through the reactor, small packets of fluorous phase aggregate along the reactor walls, forming “buds” (Figure 8c). These buds grow and eventually break off into smaller, discrete segments upon reaching a critical volume. This leads to a large number of small fluorous segments distributed throughout the length of the reactor. These experiments demonstrate that the reversal of the continuous phase leads to rapid disappearance of the fluorous phase, removing the barrier to dispersion between the carrier solvent and the reaction segment. It may be possible to slow the disappearance of the fluorous barrier by utilizing short residence times, low flow rates, carrier solvents with low interfacial tension values, and long fluorous spacers. However, it is difficult to predict the correct parameters because of nonuniform flow patterns and uncontrolled loss of fluorous phase during sample preparation. Summary of Dispersion Results. These results show that compartmentalized flow employing a reaction segment and a carrier solvent segment separated by a fluorous spacer segment can lead to dispersion via mixing of the carrier solvent and the reaction segment in both stainless steel (Hastelloy) and polymer tubing. The nature of the continuous phase can change with the nature of the reactor material, but in each case we observed that the fluorous barrier failed to prevent communication between the reaction and carrier segments. Since concentration driving forces control the reaction rate, dilution of the reaction segment by the carrier solvent may provide misleading information about the intrinsic reaction kinetics. Moreover, mixing of the reaction components with the carrier solvent may lead to other undesirable effects such as reagent precipitation and reactor clogging or even reaction quenching, dictated by the chemical compatibility of fluids. The extent to which observed dispersion patterns influence reaction performance ultimately dictates how viable compartmentalized flow methods will be for rapid reaction screening, and minimizing dispersion effects may be key to successful translation of results from the rapid screening platform to other modes of flow or batch operation. Our studies suggest that dispersion effects can be mitigated by a variety of techniques, such as the use of large reaction segments, low flow rates, short residence times, low-viscosity continuous phases, and systems with small interfacial tension. Indeed, most of the published literature on this reactor system employs short residence times and utilizes rapid reactions, suggesting that this reactor can be effective when the reaction rate outpaces the rate of dispersion. This suggests that functional operation of this reactor requires predictive modeling of dispersion rates for each reaction solvent, temperature, slug length, and flow rate as well as a prior

Figure 8. (a) Perfluorodecalin (clear) and RB-doped methanol (pink) in PFA tubing. (b) Shrinking and displacement of the rear fluorous phase, leading to mixing of the carrier solvent (pink) with reaction segment (blue). (c) Examples of “budding” and “breaking” as the carrier solvent dispersed phase (pink) displaces the perfluorodecalin continuous phase (clear). (d) Example of the methanol reaction segment (blue) when perfluorodecalin (clear) was used as a carrier solvent.

On the basis of the previously discussed model with perfluorodecalin as a thin film of thickness df and volume Vf along the walls of the reactor, the volume of the fluorous phase will decrease as Vf increases, until the perfluorodecalin phase disappears entirely when Vf = Vfluor (where Vfluor is the volume of the fluorous segment). More notably, the high viscosity of perfluorodecalin is expected to give a thicker film, df = 30−125 μm (0.2−1.5 mL/min, σ = 2.5 dyn/cm). Thus, we anticipate a rapid loss of the fluorous phase, particularly at high flow rates. Experimentally, several consistent trends were observed as the segment progressed through the reactor11 (Figure 8b): (a) The length of the rear fluorous phase decreased, and eventually this phase was no longer visible. (b) After the rear fluorous phase was no longer visible, mixing between the reaction segment and carrier solvent occurred. F


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Figure 9. (a) Conditions of model Suzuki coupling and flow parameters. (b) Comparison of conversions for different conditions and flow rates. Error bars represent one standard deviation.

Table 1. Trifluoromethylation of heterocyclesa

flow

batch

substrate

conversion

selectivity

conversion

selectivity

4-acetylpyridine ethyl-2-picolinate methyl nicotinate 3-amino-2-cyanopyridine 4-cyanopyridine 4-picoline

27% 29% 19% 37% 17% 27%

2.3:1 C3:C2 4.2:1.5:1 C5:C3:C4 C6 only 1:1.1 C4:C6 3:1 C3:C2 2.1:1 C3:C2

28% 29% 19% 33% 24% 29%

2.2:1 C3:C2 5.0:2.0:1 C5:C3:C4 C6 only 1.2:1 C4:C6 3:1 C3:C2 2.2:1 C3:C2

a Reaction conditions: 42.9 mM substrate, 85.7 mM (2 equiv) zinc trifluoromethanesulfinate, 128.6 mM (3 equiv) tert-butyl hydroperoxide, DMSOd6, 700 μL total reaction volume. Reactions were quenched after 20.0 min. Conversions and selectivities were determined by NMR spectroscopy. The flow conditions were the two-phase operation described as condition C in Figure 9.

adaptation is meant to allow the chemist to focus on the chemistry, not operational details such as dispersion, when using this instrument. Influence of Dispersion on Reactivity. In order to provide a practical test of the adapted system, a model Suzuki coupling of phenylboronic acid and 4-bromotoluene was performed under the three different types of flow conditions (Figure 9a). This study also was intended as direct probe of the influence the previously studied dispersion effects have on reactivity. The Suzuki coupling was studied under three reactor setups, conditions A, B, and C (Figure 9a.) Condition A, which uses stainless steel (Hastelloy) tubing, consists of the standard recommended three-phase operation of the Conjure reactor, with a dispersed fluorous phase separating the reaction segment from the carrier solvent. Front-to-back dispersion patterns such as those in Figure 5 are expected under these conditions. In condition B, the role of fluorous phase is inverted by using PFA tubing with the fluorous spacer acting as the continuous phase, giving rise to flow conditions observed in Figure 8. In the third condition, the carrier solvent is replaced with the fluorous phase, resulting in a simpler two phase system. The conversion to the biaryl product after 20 min was determined under each condition at three different flow rates.13 The reactivity results are shown in Figure 9b. In condition A, the observed reactivity was highly dependent on the flow rate. At high flow rates, a significant decrease in reactivity was seen

knowledge of the intrinsic reaction rate. While possible, this process may be tedious for the chemist seeking an easy-to-use, automated reactor system. In practical operation, the extensive need to mitigate dispersion concerns can decrease the throughput of a platform designed for use in high-throughput screening. On the other hand, neglecting to consider dispersion can cloud the results from a high-throughput screen and lead to unreliable information for scale-up. Thus, we propose an alternative standard mode of operation for this Conjure reactor system that simplifies the protocol and can be used under a variety of reaction conditions. This standard will allow for the everyday process and medicinal chemist to use this reactor and others like it without the need for extensive study of dispersion behavior. The reactor can easily be modified to employ a two-phase system where perfluorodecalin serves the role of both the continuous phase and the carrier solvent (Figure 9a, condition c). The reaction segment, encapsulated as the dispersed phase, has no access to the reactor walls or to a miscible adjacent solvent. The fluorous solvent can easily be recycled from the reactor waste for reuse through a simple extraction and separation. Additionally, simple changes to the operation of the reactor allow the fluorous phase to be pumped and utilized as a normal solvent. While nonuniform flow may be lead to breakup of the reaction phase into smaller segments, this will not influence the reactivity of homogeneous, well-mixed reactions.2b This G


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Figure 10. (a) Spotfire-like plot showing the initial 4 × 6 ligand−base screen. (b) Optimization of the top performer in the ligand−base screen.

boronic acid. The final conditions, run at 120 °C, demonstrate how flow systems can be used to superheat systems, giving access to new parameter space. Overall, 58 unique reactions, each with a volume of 700 μL, were rapidly screened without the advent of reactor clogging. These studies show that the simple two-phase operation of the reactor provides a more accurate and reliable means for isolation of reaction segments than does the spacer/carrier/ reactant method. This “dispersion-free” method using fluorous carrier and PFA tubing displays several distinct advantages over using small volumes of the bracketing spacer: (a) reliable conversion data that do not vary with the flow rate (b) reactivity comparable to that of batch processes (c) decreased reactor clogging due to dispersion (d) simplification from a three-phase process to a two-phase process (e) ability to recycle the carrier solvent (f) easy separation of the reaction segment from the carrier during final analysis However, this work has only tested the system using PFA as the reactor material, which can only be operated at temperatures of 120 °C and below. Higher-temperature reactors, such as Teflon-coated steel reactors, will be required for superheating applications above this temperature. To mimic the conditions used here, it is important that any material selected for highertemperature applications will result in a continuous fluorous carrier phase.

compared with other conditions. In condition B, the conversion was highly variable, even in identical trials. While some trials reached conversion similar to that of condition C, other trials saw a marked decreased in reactivity. Higher instances of reactor clogging and larger variation in residence time distribution were also seen using condition B. The highest conversions and best reproducibility were achieved using the simplified two-compartment operation, condition C. These results suggest that the use of a two-phase system is more robust and reliable than the spacer/solvent system. As a further test of the two-phase, zero-dispersion system, a batch−flow comparison was performed. For this platform to be functional in high-throughput screening applications, it is important that results from this system can be compared directly to batch processes. For this example, the substrate scope of heterocyclic trifluoromethylation using zinc trifluoromethanesulfinate was probed using the flow reactor (Table 1). Reactions were prepared and injected as 700 μL plugs using perfluorodecalin as the carrier solvent. Reactions were collected and quenched after 20 min. The conversions and selectivities of the batch and flow processes were comparable, suggesting that the results from the flow reactor screen could be employed in a batch scale-up. Furthermore, this study shows that the results from the flow reactor represent an accurate portrayal of the inherent reactivity and that no suppression in reaction rate due to dispersion effects was seen. As a final test, the flow reactor was used to perform a rapid optimization, mimicking a likely application of this instrument in an industrial laboratory (Figure 10). This example, using the well-known Suzuki reaction, demonstrates a ground-up approach in which an initial screen of four ligands × six bases was performed. The top performer in this series, KOH with (±)-BINAP, gave an overall 12% conversion after a residence time of 20.0 min. This initial screen was designed to determine the relative conversion within a short time frame. This reaction was further optimized with respect to the concentration of base, temperature, surfactant additives, catalyst loading, and boronic acid concentration using the Conjure reactor under two-phase operation (condition C, Figure 9). After optimization, yields of up to 96% could be achieved within 20 min using extremely high loadings of boronic acid. Modest conversion (80%) could be achieved using 3 equiv of

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CONCLUSIONS This work has investigated the dispersion within two- and three- compartment systems and how this dispersion influences reactivity. An adaptation for reaction screening under zero dispersion conditions has been proposed. Small fluorous plugs cannot always act as an effective barrier to dispersion between a reaction mixture and the surrounding carrier solvent. A better understanding of dispersion effects and changing flow parameters can help minimize the influence of dispersion when small-volume spacers are used. However, when a threephase system is used, specialized conditions must be developed for each new reaction solvent, temperature, and flow rate. The H


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use of a two-phase system provides a more reliable and turnkey method for operation of the flow reactor under any nearly reaction conditions. While this study provides a practical method for operating the Conjure reactor, to the medicinal and process chemist, further studies may help expand the range of conditions available to this reactor. In our studies, we selected perfluorodecalin because of its high boiling point (140 °C), commercial availability, and low solubility in common organic solvents. However, higher-temperature reactions may require the use of high back-pressure or a different fluorous phase. Previous examples have used fluorous solvents such as FC-43, F-40, and perfluorodecalin as carrier solvents in segmented flow systems.14 Additionally, at high temperature, the solubility of some solvents and substrates within perfluorodecalin may need to be considered. Moreover, further study of methods for eliminating nonuniform flow using different fluorous phases and tubing combinations may be useful, particularly when studying nonhomogeneous reactions. Dispersion influences of other popular flow systems, such as the ASIA and AFRICA systems by Syrris, also provide another area of study. Finally, improvements such as superior automated segment detection, minimization of segment breakup, and more accurate sampling and dilution of reaction mixtures may still be needed to establish flow high-throughput screening methods. Overall, increased understanding of dispersion patterns and their influence on reactivity may help advance the practical use of high-throughput screening in flow. When dispersion is properly controlled, automated flow reactors have the potential to reduce the time and material needed to implement flow processes. Once optimal reaction conditions are determined via automated screening, reactions can be easily scaled up either through serial injections of the system or through transfer to larger flow reactors. This study may help make understanding and operation of these instruments more accessible to those within medicinal chemistry and process chemistry community.

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ASSOCIATED CONTENT

S Supporting Information *

Detailed procedures for determination of dispersion effects, experimental procedures for reactivity studies, characterization data, and videos of dyed segments in PFA reactor (AVI). This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS D.G.B. thanks Pfizer for a research grant. REFERENCES

(1) Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 1655. (b) McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384. (2) (a) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem., Int. Ed. 2011, 50, 7502. (b) Valera, F. E.; Quaranta, M.; Moran, A.; Blacker, J.; Armstrong, A.; Cabral, J. T.; Blackmond, D. G. Angew. Chem., Int. Ed. 2010, 49, 2478. (3) For reviews of pharmaceutical applications of flow, see: (a) Anderson, N. G. Org. Process Res. Dev. 2012, 16, 852. (b) MaletI


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