Continuous Liquid Vapor Reactions Part 2: Asymmetric

Subscriber access provided by TULANE UNIVERSITY

Full Paper

Continuous Liquid Vapor Reactions Part 2: Asymmetric Hydroformylation with Rhodium-Bisdiazaphos Catalysts in a Vertical Pipes-in-Series Reactor Martha Leigh Abrams, jonas buser, Joel R. Calvin, Martin D Johnson, Bradley R Jones, Gordon Lambertus, Clark R. Landis, Joseph R Martinelli, Scott A May, Adam McFarland, and James Stout Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00406 • Publication Date (Web): 31 Mar 2016 Downloaded from http://pubs.acs.org on April 5, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Organic Process Research & Development is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

Continuous Liquid Vapor Reactions Part 2: Asymmetric Hydroformylation with Rhodium-Bisdiazaphos Catalysts in a Vertical Pipes-in-Series Reactor M. Leigh Abrams,† Jonas Y. Buser,‡ Joel R. Calvin,‡ Martin D. Johnson,‡ Bradley R. Jones,† Gordon Lambertus,‡ Clark R. Landis,*,† Joseph R. Martinelli,‡ Scott A. May,‡ Adam D. McFarland,‡ and James R. Stout§ †

Department of Chemistry, University of Wisconsin—Madison, 1101 University Avenue, Madison Wisconsin 53706, United States

‡

Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States

§

D&M Continuous Solutions, LLC, Greenwood, Indiana 46143, United States

1 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 31

Table of Contents Graphic


Page 3 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Abstract: Asymmetric hydroformylation (AHF) of 2-vinyl-6-methoxynaphthalene demonstrates important design characteristics of a vertical pipes-in-series plug flow reactor (PFR). The regioand enantioselectivity of the AHF reaction provide a chemical probe of gas-liquid mixing in a flow reactor for comparison with well-stirred batch reactors. Results obtained with the flow reactor compare favorably to those obtained in batch. Thus, AHF provides an efficient, in-flow enantioselective synthesis of (S)-Naproxen.

Keywords: flow chemistry, hydroformylation, gas-liquid reactions

Introduction Some reactions have high intrinsic risk – reactions that involve high pressures, toxic or explosive reagents, or strong exotherms, for example – but are potentially useful for the synthesis of pharmaceutical and other fine chemicals. Enantioselective hydroformylation, the reaction of H2 and CO with alkenes in the presence of catalytic rhodium complexes of chiral ligands, is such a reaction. Recent literature provides good examples of highly selective and active catalysts for the production of a variety of chiral aldehydes via atom-efficient hydroformylation.1

For

example, the enantioselective hydroformylation of 2-vinyl-6-methoxynaphthalene in the presence of catalysts containing chiral bis(diazaphospholane) (BDP) ligands (Figure 1) effects high regioselectivity (>10:1) and enantioselectivity (>90%) with high catalyst turnover frequencies (>100 hr-1) and high substrate:catalyst loading.2 Oxidation of the resulting aldehyde to the carboxylic acid provides an attractive route to Naproxen (Scheme 1).3



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 31

Figure 1. Bisdiazaphospholane (BDP) ligand used in asymmetric hydroformylation

Scheme 1. Proposed efficient synthesis of (S)-Naproxen Although hydroformylation routes for the synthesis of Naproxen have been demonstrated, none are so highly regio- and enantioselective nor are they demonstrated in flow reactors.4 Hydroformylation approaches may also be viewed as less desirable due to safety issues associated with the use of synthesis gas (CO/H2).5,6 Transformations with high intrinsic scale-up risk, such as hydroformylation, potentially are well suited to continuous flow reactor technologies.7 One of the challenges of performing gas-liquid reactions in flow is effecting good mixing of the gaseous and liquid reagents. This challenge is particularly critical for aryl alkene hydroformylation because the product regioselectivity and enantiomeric purity have been demonstrated to be very sensitive to the partial pressure of CO.8 Under conditions of poor mass transport between gas and liquid phases, the concentration of CO in solution will be depleted relative the Henry’s law values and could result in degraded selectivity.

Conversely, the


Page 5 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


observed selectivity of hydroformylation in flow reactors is a sensitive potential probe of gasliquid mass transport. In this paper we report results for hydroformylation of styrene and 2-vinyl-6methoxynaphthalene as catalyzed by Rh(BDP) complexes in flow reactors. The overall plan begins with brief contextual overviews that are followed by descriptions of the flow reactor, special flow considerations, and benchmarking with well-stirred batch reactors. The remainder of the paper describes results for the AHF of 2-vinyl-6-methoxynaphthalene in flow. We note that a companion paper describes details of the reactor design, construction, and properties. Results and Discussion Asymmetric Hydroformylation as a Probe of Gas-Liquid Mixing in Flow Reactors. Previously, Landis et al. demonstrated that the regio- and enantioselectivity of styrene hydroformylation as catalyzed by rhodium(bisdiazaphospholane) complexes are sensitive to the CO partial pressure, with low partial pressures giving low selectivity2,8b This observation raises concerns that the rate of gas-liquid mixing in a flow reactor may not be sufficiently fast to maintain equilibrium gas concentrations, resulting in low effective partial pressures and low selectivities. It is not easy to measure dissolved gas concentration operando in a flow reactor. However, one can use the observed selectivity as a sensitive measure of the effective gas pressure during the reaction. In flow, various parameters influence the steady-state gas concentrations including partial gas pressure, gas flow rates, catalyst concentration, and alkene concentration. These parameters were systematically explored. Through such explorations we anticipated being able to smoothly transition a hydroformylation developed in batch to a continuous flow process. Using NMR to Further Characterize and Understand Hydroformylation.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 31

Independently, Eli Lilly and the Landis group at UW-Madison have been developing related approaches to in situ monitoring and modeling of reactions using NMR techniques. The Lilly group has developed a system that circulates solutions from reactors through the NMR probe (react NMR) and other analytical instrumentation. The current instrument configuration can accommodate pressures up to 1000 psi.9 This enables heteronuclear NMR data acquisition for pressurized reactions above and below room temperature. This instrument was used to profile the hydroformylation of styrene with the Rh-BDP catalyst (Figure 2).

Dissolved hydrogen

concentration was used as a surrogate for CO and instantaneous b:l was extracted and compared to relative hydrogen concentration. During heating of the reaction (40 60 °C) the drop in [H2] (corresponding to a drop in [CO]) correlates to a simultaneous drop in instantaneous b:l ratio consistent with our mechanistic findings for the hydroformylation of aryl alkenes.8a This helped illustrate the impact of gas starvation on b:l ratio and provided insight into catalyst activation and reaction kinetics.

Figure 2. Instantaneous b:l ratio over a running average of 3 data points


Page 7 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The Landis group has developed the Wisconsin high pressure NMR reactor (WiHP-NMRR) in which the reaction takes place in a high pressure NMR tube that is continuously agitated by circulation of the reactant gases.10 WiHP-NMRR was used to profile the hydroformylation 2vinyl-6-methoxynaphthalene with the Rh-BDP catalyst and allowed for direct comparison to the flow runs (vide infra). Reactor description Because of our concerns for good gas-liquid mixing and scalability from small volume research to production scales, a vertical-bubble-flow-pipes-in-series reactor type was selected. The vertical pipes in series reactor (Figure ) is designed for vapor liquid reactions with long residence times (2-20 h). There are two regimes in this design, a segmented flow regime in small diameter tubing which connects the vertical pipes which operate as bubble flow regimes.

Figure 3 Schematic for Vertical Pipes-in-Series reactor employed for flow AHF.

While commercial scale versions of this reactor design could have vertical pipes that exceed 6m in length with >5 cm pipe diameter (depending on intended volume), the smallest research scale reactors use miniature pipes (Figure ). The research scale continuous reactor consisted of 20 vertical bubble flow pipes in series, connected by small diameter tubing. Each pipe was 8 mm inside diameter (i.d.) and 7.3 mm tall, with 1 mm tall conical ends on the top and bottom. Each 7 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 31

connecting tube was 3.7 m long and 0.56 mm i.d. One of the 0.3 ml vertical pipes is shown in Figure a.

Figure 4. Pictures of the flow reactor featuring one of the mini-pipes (a), the reactor partially removed from the oil bath (b), and the full reactor after removal from the oil bath (c), which distorted the vertical pipes.

The reactor was designed to give long residence time in the bubble flow pipes, targeting mean hydraulic residence time (τ) adjustable between 0.5 to 12 hours and to give high vapor-liquid mass transfer rates in the 0.56 mm i.d. connecting tubes. This was done by achieving very small liquid segments flowing through the small diameter tubing. Most of the flow hydroformylation experiments used about 8 hours τ. The total reactor volume was 23.8 ml. Volume in the vertical up flow bubble pipes was 6 ml and volume in the 0.56 mm i.d. connecting tubes was 17.8 ml. Vertical pipes were large enough diameter so that the gas bubbled up through the liquid without pushing liquid out the top. The bubble pipes operated almost completely liquid filled, while the 0.56 mm i.d. connecting tubes operated mostly vapor filled, for example 90-93% vapor filled at baseline conditions. The top of the reactor pulled up partially out of the constant temperature oil bath is shown in Figure b, 8 ACS Paragon Plus Environment

Page 9 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


showing some of the 0.3 mL vertical upflow pipes. The entire flow reactor is shown in Figure c after removal from the oil bath which distorted the reactor. A full, detailed description of the reactor and its development is discussed in the companion paper.11

The reactor was constructed to meet the following design criteria: 1. The ability to significantly change syngas equivalents or reactor pressure (up to 1400 psi) without significantly changing τ and 2. Small liquid holdup volume, for example 8 ml, to minimize material consumption during research development. 3. Low axial dispersion, with target Levenspiel axial dispersion number D/uL = 0.015.12 4. The ability to take representative samples at intermediate sample points along the length of the PFR, to generate conversion versus τ data. 5. Optional catalyst/ligand pre-activation in flow. Pre-activation was achieved by mixing catalyst/ligand with syngas at reaction pressure and elevated temperature for controlled amount of time, for example 1 hour. Valves were installed so that the operator could switch to either flow through pre-activation tubing section or bypass it. Catalyst molar flow rate was independent of the amount of solvent that strips off into the syngas in the pre-activation section, because of the segmented flow in 0.56 mm i.d. tubing. The preactivation loop was submerged in a separate constant temperature oil bath so that preactivation temperature could be set independently from reaction temperature. Flow Considerations



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 31

The development of any continuous reaction involves some batch development. In the case of vapor liquid reactions, the screening of solvents, ligands, pressure, and understanding of reaction kinetics are best done in batch in most cases. The processes can be applied to flow where other factors may be tested such as mixing, vapor flow rate, timing of reagent and catalyst additions and heat-up, and the impact of gas mixtures. Unlike batch processing however, continuous processes do require some additional considerations such as understanding of solubility of reagents, intermediates and product, measurement of residence time, accounting for thermal expansion of solvents and solution stability to name a few. Solution stability of the reagent feeds is not often examined in batch since starting materials or catalysts can be charged directly to batch tanks. However, any change in composition of a feed solution will result in variable (nonsteady state) results in flow. An interesting example of a solution stability problem was observed during preliminary work with styrene. As is typical in sensitive catalytic reactions, solvents and solutions of reagents are degassed to remove oxygen which can be detrimental to the catalyst.

When styrene was

degassed and held in the dry box we observed that the material became viscous over time with loss of potency.13 When the source bottle of styrene (non-degassed) was examined the material was free flowing with no signs of polymerization.

Upon investigation, we learned that

polymerization of styrene is inhibited with 4-tert-butylcatechol (TBC).

However, TBC is

rendered ineffective in the absence of oxygen and polymerization will proceed as if no inhibitor were present.14 This poses an interesting challenge since oxygen, a requirement for stabilizing the reagent, could also degrade the catalyst. In this case, styrene would need to be degassed just prior to running in flow or degassed in-line as part of the continuous process itself.15


Page 11 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Fortunately, we did not observe this degradation trend in the case of 2-vinyl-6methoxynapthalene.

Table 1. Initial hydroformylation of 2-vinyl-6-methoxynapthalene with Rh-bisdiazaphospholane catalysts in Endeavor reactor.a

[Rh] Conv. S/C B:Lb ee (mM) (%) 6 hours 0.06 10,000 10.8 16 77 12 hours 0.06 10,000 27.2 19 78 6 hours 0.1 6,000 32.5 13 80 6 hours 0.4 1,500 91.5 20 82 a [2-vinyl-6-methoxynapthalene]0 = 0.6 M, reactions performed in toluene at 400 psi, 60 oC. All values determined by HPLC. bValues corrected to NMR values. Time

As preparation for flow reactions, we investigated the rate and selectivity of hydroformylation in well-stirred batch reactors. The results are summarized in Table 1. Our goal was to identify conditions that yield an approximately 2 hour half-life, which would lead to reasonable conversions with a 6 hour residence time in a flow reactor. Although the hydroformylation reaction can be run successfully at very high substrate:catalyst ratios (e. g., 10,000:1), the 1500:1 loading ratio gave the conversions desired and was used as a baseline for subsequent flow experiments. With initial reaction conditions in hand, we turned our attention toward the effect temperature has on the reaction. We evaluated the hydroformylation reaction at five temperatures, with results shown in Table 2. The branched:linear ratio (B:L) and enantiomeric excess (ee) were found to be dependent on the temperature. The branched selectivity decreased with increasing temperature, and ee increased slightly before declining at higher temperatures.16 We observed 70 o

C to allow for high enantioselectivity without much loss in branched selectivity.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 31

Table 2. Hydroformylation of 2-vinyl-6-methoxynapthalene by Rh-BDP in Endeavor Reactor at various temperatures.a

Temp Conv. B:Lb ee (oC) (%) 1 40 48.7 23.6 79.8 2 60 93.2 19.8 85.3 3 70 99.2 18.6 89.0 4 80 99.2 15.4 73.0 5 100 99.2 8.8 28.6 a 6 hour reaction, [2-vinyl-6-methoxynaphthalene]0 = 0.502 M, [Rh] = 0.373 mM, reactions performed in toluene, 400 psi CO/H2. bValues corrected to NMR values.

The continuous reactor was designed to be plug flow such that conversion versus time in the continuous reactor should match batch, if mass transfer is the same in both. Thus, we studied the order of the reaction rate in the concentration of 2-vinyl-6-methoxynaphthalene. A series of experiments were carried out in the Wisconsin High-Pressure NMR Reactor (WiHP-NMRR), a reactor capable of maintaining constant temperature and concentration of dissolved gases in magneto, in order to determine the order of the substrate in the reaction (Figure ).10 The reaction was observed to be approximately first order in 2-vinyl-6-methoxynapthalene at 70 °C, 160 psi CO/H2 (1:1), and a substrate:catalyst ratio of 1345:1.


Page 13 of 31

100 90 80 Conversion (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


70 60

s.m. remaining

50

branched prod.

40

109.1e-13.67x

y= R² = 0.9942

30

linear prod.

20 10 0 0:00:00

1:00:00

2:00:00

3:00:00 4:00:00 Time (h)

5:00:00

6:00:00

Figure 5. Batch hydroformylation profile monitored by WiHP-NMRR. [2-vinyl-6-methoxynaphthalene]0 = 0.502 M, [Rh] = 0.373 mM. The solid black line represents decay of starting material according to a single exponential.

In preparation for our flow studies we performed an examination of reaction selectivity as a function of gas pressure in better-stirred (than the Endeavour reactors) Parr reactors with purified ligand. These results are show below in Table 3. As expected we see that the branched:linear ratio of the product systematically degrades (from 21.3 to 11.6) as the pressure is decreased (from 800 to 150 psig). However, the enantioselectivity variation is smaller and not systematic.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 31

Table 3. Hydroformylation of 2-vinyl-6-methoxynaphthalene by Rh-BDP in Parr reactor at various pressures.a

PH2/CO Conv. B:Lb ee (psi) (%) 1 800 99.3 21.3 85.4 2 400 99.3 18.4 90.0 3 150 99.3 11.6 86.6 a 6 hour reaction, [2-vinyl-6-methoxynaphthalene]0 = 0.502 M, [Rh] = 0.373 mM, reactions performed in toluene, 70 oC. All values average of 2 runs, determined by HPLC. bValues corrected to NMR values. We next sought to observe whether pre-activating the catalyst, allowing the pre-catalyst solution to react with CO/H2 to generate the catalytic resting state RhH(BDP)(CO)2 prior to introduction of alkene, impacts the selectivity. The flow reactor was constructed to allow for optional pre-activation of the catalyst, should the selectivity be improved. We evaluated preactivated catalyst in batch and the results are shown in Table 4. The state of catalyst preactivation had little effect on the conversion, branched:linear selectivity,17 and enantioselectivity of the reaction.

Table 4. Hydroformylation of 2-vinyl-6-methoxynaphthalene by Rh-BDP in Endeavor reactor at various pressures and temperatures, with and without pre-activation.a

PH2/CO PreTemp. Conv. ee B:Lb c o (psi) activated ( C) (%) 1 150 Yes 60 83.8 17.6 90.9 2 400 Yes 60 81.0 22.8 91.1 3 400 60 73.3 27.1 91.4 5 150 Yes 70 98.3 11.2 86.5 6d 150 70 99.3 11.6 86.6 7 400 Yes 70 95.6 18.9 89.9 8d 400 70 99.3 18.4 90.0 a 3 hour reaction, [2-vinyl-6-methoxynapthalene]0 = 0.502 M, [Rh] = 0.373 mM, reactions performed in toluene. All values average of 3 runs, determined by HPLC. bValues corrected to NMR values. cCatalyst was pre-activated by stirring under 150 psi CO/H2 for 15 hours at 60 oC. d Entry reproduced from Table 3. Asymmetric Hydroformylation in Flow


Page 15 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


After establishing catalyst performance in batch experiments, we explored AHF in the flow reactor. We evaluated the same conditions as batch experiments in flow, shown in Table 5. We observed high branched:linear selectivity, 27:1, and high ee, 92%, at 400 psi. Pre-activation of the catalyst with the pre-activation coil gave results similar to bypassing the preactivation coil. The pressure of the flow system was increased to 800 psi, from the baseline of 400 psi, upon which we saw a drop in both branched:linear selectivity and enantioselectivity. The reasons for these decreases remain unclear. Lowering of the pressure to 150 psi, from 400 psi, led to anticipated

decrease in

branched:linear selectivity (to

13:1) alongside increase in

enantioselectivity (to 89%) which is near to the batch conditions in the Parr reactor (11.6:1 b:l, 86.6% ee). After returning to the initial flow conditions of 400 psi without pre-activation, branched:linear selectivity increased, however did not recover to its initial value.18

Table 5. Summary of steady states achieved during asymmetric hydroformylation of 2-vinyl-6-methoxynaphthalene in flow with Rh-BDP catalysts.a

Residence Conv. PH2/CO B:Lb ee (psi) time (h) (%) 1 400 8.3 98 27 92 2c 400 8.2 98 27 92 3 800 8.2 97 20 80 4 150 7.5 98 13 89 5 400 8.5 98 20 90 a [2-vinyl-6-methoxynaphthalene]0 = 0.502 M, [Rh] = 0.373 mM, reaction carried out in toluene, 70 oC, all values determined by HPLC. bValues corrected to NMR values. cWith catalyst pre-activation coil enabled, catalyst and syn gas were mixed at 60 oC for 1.3 hours prior to introduction of the substrate.

The time course for the flow reactor is shown in Table 5. The first week, the reactor ran continuously for about 100 hours. The reactor was stopped and sat filled and isolated for 95 hours. Then, the reactor was re-started and ran for 15 hours. It was stopped for 8 hours to



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 31

conserve material because we did not want to run out of feeds in the middle of the night. Finally, the reactor ran for another 17 hours on the final day.


Page 17 of 31


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 31

Figure 6. Time course for asymmetric hydroformylation of 2-vinyl-6-methoxynapthalene in flow over the course of six transitions and five steady states.

Figure 6a shows a timeline of the reactor performance. The steady states are labeled as SS# and are preceded by a transition labeled T#. The first four transitions and steady states are shown in Figure 6b and the final two shown in Figure 6c. Residence times are indicated and shaded regions are drawn as 1.5•τ. Residence times (τ) are calculated from flow with a non-reactive tracer. In Figure 6b, the first four transitions and steady states are shown. In transition 1 and steady state 1, p = 400 psi. In transition 2 and steady state 2, p = 400 psi and the pre-activation coil was enabled. During transition 3 and steady state 3, the catalyst was turned off to observe the decrease in conversion. In Transition 4 and steady state 4, the catalyst flow was resumed and the system pressurized to 800 psi without use of the pre-activation coil. The reactor was then turned off for approximately 4 days. In Figure 6c, the reactor was resumed and pressurized to 150 psi for transition 5 and steady state 5. The reactor was then shut off again briefly before it was restarted at 400 psi in transition 6 and steady state 5 to return to initial conditions. A comparison between the enantioselectivity and regioselectivity of the reaction at various pressures in batch and flow is shown in Figure 7. Generally, the selectivity between batch and flow is similar, suggesting good gas/liquid mixing in the flow reactor.


Page 19 of 31

a

30 Batch (Parr) Flow Flow (Final)

branched:linear

25 20 15 10 5 0 150

400

800

Pressure (psi)

b

94 Batch (Parr) Flow Flow (final)

92 90 88 86

ee

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


84 82 80 78 76 74 150

400

Pressure (psi)

800

Figure 7. Comparison of regioselectivity (a) and enantioselectivity (b) between batch reactions performed in a Parr reactor and reactions carried out in flow. The reactor’s design enables sampling along the path of the flow reactor; such sampling yields time profiles of the reaction. Conversion of 2-vinyl-6-methoxynaphthalene with time in the flow reactor is compared with conversion data collected from the WiHP-NMRR reactor in Figure 8. As expected, the rates of the reactions were similar between batch and flow methods.



a

100 90

Conversion (%)

80 70

400 psi WiHP-NMRR w/pre-act

60

400 psi Flow (initial)

50

400 psi Flow w/ pre-act

40

400 psi Flow (final)

30 20 10 0 0:00:00

1:30:00

3:00:00

4:30:00

6:00:00

7:30:00

time (h)

b

100 90 80

Conversion (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 31

70 60 50 161 psi WiHP-NMRR w/ pre-act

40 30

150 psi Flow

20 10 0 0:00:00

1:30:00

3:00:00

4:30:00

6:00:00

7:30:00

time (h)


Page 21 of 31

c C

100 90 80

Conversion (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


70 60 745 psi WiHP-NMRR w/ pre-act

50 40

800 psi Flow

30 20 10 0 0:00:00

1:30:00

3:00:00

4:30:00

6:00:00

7:30:00

time (h)

Figure 8. Comparison of conversion versus time in batch (WiHP-NMRR) and in flow at 400 psi (a), 150 psi (b), and 750 psi (batch) versus 800 psi (flow) (c).

Oxidation

Scheme 2. Asymmetric hydroformylation of 2-vinyl-6-methoxynapthalene followed by Pinnick Oxidation. Following development of AHF in flow, we sought to establish conditions for oxidation of the resulting aldehyde into its corresponding acid, naproxen. We elected to use a Pinnick oxidation due to its mild nature and relatively pH neutral conditions.4b,19 Following AHF on a 1 mmol scale, oxidation of the aldehyde yielded Naproxen in 82% overall yield (based on 2-vinyl-6methoxynapthalene). Conclusion



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 31

This paper demonstrates in-flow, high pressure asymmetric hydroformylation of 2-vinyl-6methoxynaphthalene using the research scale pipes-in-series plug flow reactor described in the companion paper. Implementation of AHF in flow began by investigating the reaction in wellstirred batch reactors. We targeted reaction conditions that would allow for high conversions in our flow reactor with approximately 8 hour residence times. Screening studies reveal that a reaction temperature of 70 oC led to high conversion and enantioselectivity while maintaining good regioselectivity. Increased pressure of synthesis gas was found to lead to increased regioselectivity, but the effects on enantioselectivity were less clear. Catalyst pre-activation had little effect on the rate or selectivity of the reaction. The flow reactor was run for a total of 130 hours and continuously for 100 hours over six transitions and five steady states. The selectivity was comparable between batch and flow, indicating effective gas-liquid mixing in the pipes-in-series flow reactor. Pre-activation of the catalyst did not impact the selectivity indicating that catalyst may be introduced into the reactor directly as a the Rh(acac)(BDP) precursor. Examination of conversion along the flow reactor showed the rates and order in substrate (first-order) to be the same as batch reactions. Significantly this study 1) demonstrates that careful attention to flow reactor can result in good gas-liquid mass transport, even on small-volume research scales, for a reaction that is sensitive to partial pressures of gaseous reagents 2) illustrates the utility of operando high pressure NMR in benchmarking catalytic rates and selectivities for optimization of flow reactors and 3) demonstrates that application of enantioselective hydroformylation, a high pressure reaction with toxic and flammable reagents, can be performed safely and effectively in a pharmaceutical environment. This work should facilitate the application of enantioselective hydroformylation in pharmaceutical production.


Page 23 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Experimental Section General Considerations. Synthesis gas refers to a mixture of 1:1 CO/H2 unless otherwise stated. Precatalyst Preparation. The metal-ligand complex or “pre-catalyst” was prepared by adding a solution of Rh(acac)(CO)2 to a vial containing the (R,R,R)-BisDiazaphos-SPE ((R,R,R)-BDP) ligand inside a glovebox. A stock solution of Rh was formed by dissolving Rh(acac)(CO)2 (23.1 mg, 0.0895 mmol) in 4.455 mL of degassed toluene, giving a yellow solution, [Rh(acac)(CO)2] = 20.09 mM. Inside the glove box, a vial was charged with 109.4 mg (R,R,R)-BDP (94% potent, 0.0784 mmol). To the vial was added 3.5655 mL of the Rh stock solution (0.0716 mmol Rh, 1.1 eq. ligand). The resulting solution was diluted with 10.695 mL toluene to give a pre-catalyst solution of 5.02 mM Rh(acac)((R,R,R)-BDP). 6-Methoxy-2-vinylnaphthalene synthesis.20 2-bromo-6-methoxynaphthalene (40.01 g, 168.74 mmol), tetra-N-butylammonium bromide (27.24 g, 84.51 mmol), palladium (II) acetate (0.378 g, 1.68 mmol) and bis(4, 6-dimethyl-3-sulphonatophenyl)(2,4-dimethylphenyl)phosphine, disodium salt monohydrate (1.96 g, 3.38 mmol) were added to a 1L autoclave. Acetonitrile (300 mL) was added to the reactor followed by N,N-diisoprpylethylamine (60 mL, 344 mmol) which was rinsed in with 20 mL of additional acetonitrile. Once the reagents and solvents were added the 1L autoclave was purged with ethylene then pressurized to 150 psi and heated to 90 °C. Once at temperature the reaction pressure was 215 psi. The reaction was stirred for 16.5h before cooling and venting. Analysis by GCMS indicated that the reaction was complete. The crude reaction was diluted with ethyl acetate (1.25L) and filtered through celite. The resulting organic solution was washed with water (2 x 300 mL), 0.25N HCl (3 x 300 mL) and 23 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 31

water (300 mL). The water wash resulted in an emulsion that required the addition of ethyl acetate (100 mL) to obtain a clean separation. The resulting organic solution was treated with activated carbon and magnesium sulfate prior to filtration over a layer of celite and silica gel. A layer of green/ yellow was retained by the silica layer. The solids and filter cake were rinsed with an additional 500mL EtOAc prior to concentration to a white solid (27.3 g, 86%). 6Methoxy-2-vinylnaphthalene was used directly as crude product was used directly in hydroformylation reactions. 1H NMR (400 MHz, CDCl3) δ 7.65-7.72 (m, 3H), 7.56-7.61 (m, 1H), 7.08-7.14 (m, 2H), 6.82 (dd, J = 17.5, 11 Hz, 1H), 5.80 (d, J = 17.5 Hz, 1H), 5.23 (d, J = 11 Hz, 1H), 3.86 (s, 3H) 6-Methoxy-2-vinylnaphthalene solution preparation: A pressure bottle was charged with 2vinyl-6-methoxynapthalene (13.31 g, 72.26 mmol). 120 mL degassed toluene was added and the solution agitated to dissolve solids. The mass of the solution (116.56 g) and density (0.8736 g/mL) were determined. The concentration of the olefin solution was determined to be 0.542 M. Method for Endeavor Reactor. To a glass reaction tube was added 1.795 mL of 0.542 M olefin solution (0.973 mmol) and 0.1443 mL of 5.02 mM pre-catalyst solution (0.724 µmol). [Rh] = 0.373 mM, [2-vinyl-6-methoxynaphthalene]0 = 0.502 M, 1344:1 s:c. The endeavor reactor was equipped with stir-paddles, sealed, and each well pressurized and heated to the desired conditions. The reactions were allowed to proceed for the time indicated. After the reaction time, the wells were cooled and depressurized, then analyzed by HPLC. Method for Wisconsin High-Pressure NMR Reactor (WiHP-NMRR). To a pressure bottle reactor was added 0.300 mL of 3.108 mM precatalyst (0.932 µmol) solution in toluene-d8 inside a glovebox. The vessel was sealed and removed from the glove box. Following 5 fill (150


Page 25 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


psi)/purge (20 psi) cycles with synthesis gas, the vessel was filled to 150 psi and placed in an oil bath at 60 oC overnight. The vessel was allowed to cool, depressurized, and brought into a glovebox. Inside the glove box, the solution was transferred to a syringe, and a the vessel rinsed with enough toluene to result in 0.500 mL total (ca. 0.200 mL). The WiHP-NMRR apparatus was warmed to 70 oC and 1.65 mL of 0.762 M 2-vinyl-6-methoxynaphthalene (1.26 mmol) in toluene-d8 was injected, followed by 0.35 mL toluene-d8 as a chaser. The reactor was pressurized to 141 psi of synthesis gas. The solution was allowed to warm and was saturated with synthesis gas by acquiring one NMR experiment (67% active circulator). The activated catalyst and toluene-d8 chaser (0.500 mL total) were loaded into the high-pressure injection apparatus. The catalyst was injected, and the pressure of CO/H2 increased to 161 psi to allow for depleted gas to be replenished. After injection, [Rh] = 0.373 mM, [2-vinyl-6-methoxynaphthalene]0 = 0.503, 1348:1 s:c. Method for Parr Reactor. Inside a glovebox, two 7 mL glass vials were each charged with 2.00 mL of 0.542 M olefin solution (1.08 mmol) and 0.160 mL of 5.02 mM pre-catalyst solution (0.803 µmol). [Rh] = 0.372 mM, [2-vinyl-6-methoxynaphthalene]0 = 0.500 M, 1344:1 s:c. Two additional 7 mL vials were charged with 3 mL of degassed toluene to help saturate the Parr reactor with solvent. All vials were sealed with septa and an 18 gauge needle inserted to allow for gas to enter/leave. The vials were loaded into the Parr reactor, the reactor sealed, and then removed from the glovebox. The gas line was purged 4 times with dinitrogen and the Parr purged once with synthesis gas (ca. 200 psi). The Parr was pressurized to the desired pressure and heated to the desired temperature. After the reaction, the Parr reactor was cooled with a water bath, vented, and purged 3 times with dinitrogen before returning to the glove box. The samples were analyzed by HPLC.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 31

Method for Flow. Olefin and pre-catalyst solutions prepared as described above were pumped separately. The olefin solution was loaded into the syringe of one pump, and the precatalyst solution was loaded into a feed coil for a second pump. The second pump was filled with toluene. Toluene from the second pump pushed the pre-catalyst solution out of the feed coil and into the reactor. The pre-catalyst flow was set to 0.00124 mL/min and the olefin flow set to 0.01546 mL/min giving a substrate:catalyst ratio of 1346:1. Liquid pumping was achieved with high pressure ISCO® 100D syringe pumps. Baseline condition was 400 psig reaction pressure and gas flow rate 0.200 mmol/min, leading to 12 equivalents of CO and 12 equivalents of H2. The 800 psig flow reaction was done with 39 equivalents of each gas, and the 150 psig flow reaction was done with 10 equivalents of each. The final flow steady state conditions returned to 400 psig reactor pressure but used 15 equivalents of each gas. Gas was introduced to the precatalyst flow shortly before being combined with the olefin flow. Gas mixed with the precatalyst solution, and then the 2-phase gas-liquid stream mixed with olefin solution, in a simple Tee mixers with 0.56 mm i.d. In the case of pre-activation, the pre-catalyst and gas are routed through a “pre-activation loop” where they flow through a 0.56 mm i.d. tube at desired temperature for approximately 1.3 hours, before being combined with the olefin feed. On the back end of the flow reactor, the exiting solution is diluted with toluene from a separate pump at a rate of 0.333 mL/min, resulting in 20:1 dilution. The diluted product solution was sampled by custom in-house automated system for sampling, dilution, parking the diluted sample on a switching valve for on-line HPLC, and also parking a portion of the diluted sample in a zone that was sampled by Global FIA (FloPro Sampler from Global FIA, Fox Island, Washington) fraction collector to retain all of the samples in case we decided to analyze them by off-line LC or GC.


Page 27 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Sample Monitoring. Conversion, branched:linear ratio, and enantiomeric excess were all monitored by HPLC when indicated. The sample was diluted by combining 5 µL sample with 1000 µL of diluent (80:20 hexanes:isopropanol). The samples were evaluated on a Chiralpak ID3 column with mobile phase of 3% IPA/97% hexanes and 0.1% trifluoroacetic acid with an isocratic flow rate of 0.7 mL minute. The retention times are as follows: starting material 6.2 min, branched product 1 12.0 min, branched product 2 13.5 min, and linear product 18.6 min. Method for Pre-activation. A 5.00 mM solution of pre-catalyst was prepared as described above. To an Endeavor reactor tube, inside a glovebox, was added 3.4550 g of precatalyst solution. The reactor was sealed and pressurized to 150 psi synthesis gas and heated to 60 oC. After 15 hours of reaction time, the reactor was cooled and vented. The tube was massed and 0.6179 g of toluene solvent was lost during the pre-activation. To the tube was added 713 µL toluene to replace the lost solvent. The activated catalyst was kept under atmospheric nitrogen in the glove box and found to be stable over the 3 days for which it was used. Method for Pressure Bottle. Inside a glovebox, an oven dried 15 mL Ace Glass pressure bottle equipped with a magnetic stir bar was charged with 33.3 µL of 20 mM Rh(acac)(CO)2 in THF, 40.0 µL of 20 mM (R,R,R)-Bisdiazaphos-SPE in THF, and 200 µL of neat toluene. The pressure bottle was attached to a pressure reactor head, removed from the glove box, and placed in a fume hood. The vessel was subjected to 5 pressurization (150 psi)/depressurization (20 psi) cycles with synthesis gas, then pressurized to 150 psi and placed in an oil bath at 60 oC. The solution was stirred for 45 minutes, allowed to cool, depressurized to 20 psi, and then 2-vinyl-6methoxynaphthalene (0.1899 g, 94.3, 0.972 mmol) was injected as a solution in toluene (0.90 mL). The vessel was repressurized to 150 psi synthesis gas and allowed to stir for 22 hours at 60 o

C. After the reaction, the vessel was allowed to cool and depressurized (0 psig). 27 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 31

Method for Oxidation. A procedure for the literature was modified as follows.16 Following the hydroformylation reaction, the solution was transferred to a round bottom flask and the vessel rinsed with toluene (ca. 1 mL). The solvent was removed to obtain an solid offwhite product. To the round bottom was added tBuOH (20.3 mL), and 4.9 mL 2-methyl-2butene. The mixture was vigorously stirred for 5 minutes to dissolve the aldehyde. A glass vial was charged with KH2PO4 (0.9127 g, 6.7 mmol, 6.9 eq.) and NaClO2 (0.8022 g, 7.1 mmol, 7.3 eq.). The salts were dissolved in distilled water (8 mL) and added dropwise to the stirring aldehyde solution over 18 minutes. The solution was allowed to stir for 20.5 hours. Volatiles were removed under vacuum and dissolved with water (20 mL) and saturated NaHCO3 solution (10 mL). The mixture was washed with hexane (2x12 mL) and the aqueous layer then acidified to pH 3 with HCl (3 M). The mixture was extracted with CH2Cl2 (3x 16 mL), the combined organic layers washed with water (30 mL), dried over Na2SO4 and removed in vacuo to yield 184.7 mg (82.5% yield) of a solid off-white product, (S)-Naproxen. SUPPORTING INFORMATION Supporting information includes characterization data for hydroformylation products and other materials, determination of the ligand potency, HPLC data for on-line characterization of reaction conversion and selectivity, timecourses for individual flow runs, and NMR spectra for all materials.

AUTHOR INFORMATION Corresponding Author Email: [email protected]


Page 29 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. Funding Sources This research was supported through the Eli Lilly LRAP program. ACKNOWLEDGMENT We thank Paul Milenbaugh, Ed Deweese, Ed Plocharczyk, Morgan Rosemeyer, and Jonathan Adler from D and M Continuous Solutions. Paul Milenbaugh and Ed Deweese constructed the reactor systems and custom dilution cart for online HPLC. Ed Plocharczyk advised the engineering. Morgan assisted with the axial dispersion testing and provided engineering drawings. Jonathan provided engineering drawings. We thank Richard Cope for assisting with the continuous reaction experiments. Wei-Ming Sun was co-inventor and automation engineer for the custom sampling/dilution/parking system that enabled on-line HPLC. We thank the LRAP program for financial support. Brian Haeberle did the first generation continuous reactor development work. We thank Bret Huff for leading and sponsoring the continuous reaction design and development work at Eli Lilly and Company. We thank Charlie Fry of the University of Wisconsin-Madison Instrumentation Center for assistance with the NMR instrumentation. The high pressure NMR instrumentation (WiHP-NMRR) used in this work was created by Dr. Nicholas Beach and Dr. Spring Knapp and we thank them for their valuable assistance.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 31

REFERENCES 1

a) Yu, Z.; Eno, M. S.; Annis, A. H.; Morken, J. P. Org. Lett. 2015, 17, 3264-3267;

b) Abrams, M. L.; Foarta,

F.; Landis, C. R. J. Am. Chem. Soc. 2014, 136, 14583-14588. 2

Watkins, A. L.; Hashiguchi, B. G.; Landis, C. R. Org. Lett. 2008, 10, 4553-4556.

3

a) Harrington, P. J.; Lodewijk, E. Org. Process Res. Dev. 1997, 1, 72-76. b) G. T. Whteker, J. R. Briggs, J. E.

Babin, B. A. Barner. Chem. Ind. (Dekker) 2003, 89, 359-367. 4

a) Rajurkar, K. B.; Tonde, S. S.; Didgikar, M. R.; Joshi, S. S.; Chaudhari, R. V. Ind. Eng. Chem. Res. 2007, 46,

8480-8489; 5

b) Allmendinger, S.; Kinuta, H.; Breit, B. Adv. Synth. Catal. 2015, 357, 41-45.

Hydrogen is a flammable gas with a very low ignition energy, see 5. Carbon monoxide is also a flammable gas. In

addition, CO is a poisonous gas having a binding affinity for hemoglobin >200x that of oxygen. See 6 6

a) Astbury, G. R.; Hawksworth, S. J. Int. J. Hydrogen Energy 2007, 32, 2178-2185;

b) Blumenthal, I. J. R. Soc.

Med. 2001, 94, 270-272. 7

Johnson, M. D.; May, S. A.; Calvin, J. R.; Remacle, J.; Stout, J. R.; Diseroad, W. D.; Zaborenko, N.; Haeberle, B.

D.; Sun, W.-M.; Miller, M. T.; Brennan, J. Org. Process Res. Dev. 2012, 16, 1017-1038. 8

a) Watkins, A. L.; Landis, C. R. J. Am. Chem. Soc. 2010, 132, 10306-10317;

Landis, C. R. ACS Catalysis 2013, 3, 2905-2909;

b) Tonks, I. A.; Froese, R. D.;

c) Lazzaroni, R.; Raffaelli, A.; Settambolo, R.; Bertozzi, S.;

Vitulli, G. J. Mol. Catal. 1989, 50, 1-9. 9

Buser, J. Y.; McFarland, A. D. Chem. Commun. 2014, 50, 4234-4237.

10

Beach, N. J.; Knapp, S. M. M.; Landis, C. R. Rev. Sci. Instrum. 2015, 86, 104101

11

See the companion paper and the SI for the companion paper. Levenspiel, O. Chemical Reaction Engineering; John Wiley and Sons, Inc.: New York, 1999.

12

13

See supplementary material for potency information by NMR.

14

Safe Handling and Storage of Styrene Monomer, Chevron Philips Chemical Company, 2010.

15

In a bubble flow PFR the reactive gas (syngas) can also serve as a sparging gas for oxygen ahead of catalyst feed

combination. This would not be the case for a segmented flow PFR where pockets of vapor and liquid are formed in the reactor. 16

The reason for this observation is unclear. It is possible that hydroformylation by non-enantioselective catalysts is occuring at low temperature because catalyst activation may be slow at these temperatures.


Page 31 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


17

Entry 2 and 3 show a higher b:l ratio for preactivated catalyst with similar ee. This may be due to the difficulty in measuring higher ratios accurately. From the data, it is not clear that this trend is systematic. We elected not to use the preactivated catalyst in further experiments. 18 This lack of recovery suggests that the system has changed. This could be a result of instability in one or more of the solution feeds or through accumulation within the flow reactor. 19

Bal, B. S.; Childers Jr, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091-2096.

20

6-bromo-2-vinylnaphalene is available through a number of vendors. It has also been prepared on numerous

occasions in the literature including Alacid, E.; Najera, C. Adv. Synth. Catal. 2006, 348, 2085-2091.


Continuous Liquid Vapor Reactions Part 2: Asymmetric

Recommend Documents